Ankyrin repeat and sterile alpha motif (SAM) domain-containing (Anks) protein family Phosphotyrosine-binding (PTB) domain; Both AIDA-1b (AbetaPP intracellular domain-associated protein 1b) and Odin (also known as ankyrin repeat and sterile alpha motif domain-containing 1A; ANKS1A) belong to the Anks protein family. Both of these family members interacts with the EphA8 receptor. Ank members consists of ankyrin repeats, a SAM domain and a C-terminal PTB domain which is crucial for interaction with the juxtamembrane (JM) region of EphA8. PTB domains are classified into three groups, namely, phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains of which the Anks PTB is a member. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 296 QYWQHHPEKLIFQSCDYKAFYLGSMLIKELRGTESTQDACAKMRancqKSTEQMKKVPTIILSVSYKGVKFIDATNKNII 375
Cdd:cd01274     1 TQWRHSPEKLITGSVNYEAHYLGSTEIKELRGTESTKKAIQKLK----KSTREMKKIPTIILSISYKGVKFIDATTKNLI 76

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 376 AEHEIRNISCAAQDPEDLSTFAYITKDLKSNHHYCHVFTAFDVNLAYEIILTLGQAFEVAYQLALQARKG 445
Cdd:cd01274    77 CEHEIRNISCACQDPEDLNTFAYITKDLKTDHHYCHVFCVLTVDLATEIILTLGQAFEVAYQLALRAQKS 146

SAM domain of AIDA1AB-like proteins, repeat 2; SAM (sterile alpha motif) domain repeat 2 of AIDA1AB-like proteins is a protein-protein interaction domain. AIDA1AB-like proteins have two tandem SAM domains. They may form an intramolecular head-to-tail homodimer. One of two basic motifs of the nuclear localization signal (NLS) is located within helix 5 of the SAM2 (motif HKRK). This signal plays a role in decoupling of SAM2 from SAM1, thus facilitating translocation of this type proteins into the nucleus. SAM domains of the AIDA1AB-like subfamily can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor. Additionally AIDA1AB-like proteins may participate in the regulation of nucleoplasmic coilin protein interactions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1953297527 108 DGYHPTSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELINVLKINLIGHRKRILASLGDR 172
Cdd:cd09500     1 DGNSPASVSEWLDSIGLGDYIETFLKHGYTSMERVKRIWEVELTNVLEINKLGHRKRILASLADR 65

Ankyrin repeat and sterile alpha motif (SAM) domain-containing (Anks) protein family Phosphotyrosine-binding (PTB) domain; Both AIDA-1b (AbetaPP intracellular domain-associated protein 1b) and Odin (also known as ankyrin repeat and sterile alpha motif domain-containing 1A; ANKS1A) belong to the Anks protein family. Both of these family members interacts with the EphA8 receptor. Ank members consists of ankyrin repeats, a SAM domain and a C-terminal PTB domain which is crucial for interaction with the juxtamembrane (JM) region of EphA8. PTB domains are classified into three groups, namely, phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains of which the Anks PTB is a member. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 296 QYWQHHPEKLIFQSCDYKAFYLGSMLIKELRGTESTQDACAKMRancqKSTEQMKKVPTIILSVSYKGVKFIDATNKNII 375
Cdd:cd01274     1 TQWRHSPEKLITGSVNYEAHYLGSTEIKELRGTESTKKAIQKLK----KSTREMKKIPTIILSISYKGVKFIDATTKNLI 76

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 376 AEHEIRNISCAAQDPEDLSTFAYITKDLKSNHHYCHVFTAFDVNLAYEIILTLGQAFEVAYQLALQARKG 445
Cdd:cd01274    77 CEHEIRNISCACQDPEDLNTFAYITKDLKTDHHYCHVFCVLTVDLATEIILTLGQAFEVAYQLALRAQKS 146

SAM domain of AIDA1AB-like proteins, repeat 2; SAM (sterile alpha motif) domain repeat 2 of AIDA1AB-like proteins is a protein-protein interaction domain. AIDA1AB-like proteins have two tandem SAM domains. They may form an intramolecular head-to-tail homodimer. One of two basic motifs of the nuclear localization signal (NLS) is located within helix 5 of the SAM2 (motif HKRK). This signal plays a role in decoupling of SAM2 from SAM1, thus facilitating translocation of this type proteins into the nucleus. SAM domains of the AIDA1AB-like subfamily can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor. Additionally AIDA1AB-like proteins may participate in the regulation of nucleoplasmic coilin protein interactions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1953297527 108 DGYHPTSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELINVLKINLIGHRKRILASLGDR 172
Cdd:cd09500     1 DGNSPASVSEWLDSIGLGDYIETFLKHGYTSMERVKRIWEVELTNVLEINKLGHRKRILASLADR 65

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1953297527   34 PRCPVQTVGQWLESIGLPQYENHLMANGFDNVQFMgsNVMEDQDLLEIGILNSGHRQRILQAIQLL 99
Cdd:smart00454   2 SQWSPESVADWLESIGLEQYADNFRKNGIDGALLL--LLTSEEDLKELGITKLGHRKKILKAIQKL 65

SAM domain (Sterile alpha motif); It has been suggested that SAM is an evolutionarily conserved protein binding domain that is involved in the regulation of numerous developmental processes in diverse eukaryotes. The SAM domain can potentially function as a protein interaction module through its ability to homo- and heterooligomerise with other SAM domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1953297527  37 PVQTVGQWLESIGLPQYENHLMAnGFDNVQFMGSnvMEDQDLLEIGILNSGHRQRILQAIQLL 99
Cdd:pfam00536   4 SVEDVGEWLESIGLGQYIDSFRA-GYIDGDALLQ--LTEDDLLKLGVTLLGHRKKILYAIQRL 63

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1953297527  108 DGYHPTSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEvELINVLKINLIGHRKRILASL 169
Cdd:smart00454   2 SQWSPESVADWLESIGLEQYADNFRKNGIDGALLLLLTSE-EDLKELGITKLGHRKKILKAI 62

Ankyrin repeat and sterile alpha motif (SAM) domain-containing (Anks) protein family Phosphotyrosine-binding (PTB) domain; Both AIDA-1b (AbetaPP intracellular domain-associated protein 1b) and Odin (also known as ankyrin repeat and sterile alpha motif domain-containing 1A; ANKS1A) belong to the Anks protein family. Both of these family members interacts with the EphA8 receptor. Ank members consists of ankyrin repeats, a SAM domain and a C-terminal PTB domain which is crucial for interaction with the juxtamembrane (JM) region of EphA8. PTB domains are classified into three groups, namely, phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains of which the Anks PTB is a member. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 296 QYWQHHPEKLIFQSCDYKAFYLGSMLIKELRGTESTQDACAKMRancqKSTEQMKKVPTIILSVSYKGVKFIDATNKNII 375
Cdd:cd01274     1 TQWRHSPEKLITGSVNYEAHYLGSTEIKELRGTESTKKAIQKLK----KSTREMKKIPTIILSISYKGVKFIDATTKNLI 76

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 376 AEHEIRNISCAAQDPEDLSTFAYITKDLKSNHHYCHVFTAFDVNLAYEIILTLGQAFEVAYQLALQARKG 445
Cdd:cd01274    77 CEHEIRNISCACQDPEDLNTFAYITKDLKTDHHYCHVFCVLTVDLATEIILTLGQAFEVAYQLALRAQKS 146

SAM domain of AIDA1AB-like proteins, repeat 2; SAM (sterile alpha motif) domain repeat 2 of AIDA1AB-like proteins is a protein-protein interaction domain. AIDA1AB-like proteins have two tandem SAM domains. They may form an intramolecular head-to-tail homodimer. One of two basic motifs of the nuclear localization signal (NLS) is located within helix 5 of the SAM2 (motif HKRK). This signal plays a role in decoupling of SAM2 from SAM1, thus facilitating translocation of this type proteins into the nucleus. SAM domains of the AIDA1AB-like subfamily can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor. Additionally AIDA1AB-like proteins may participate in the regulation of nucleoplasmic coilin protein interactions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1953297527 108 DGYHPTSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELINVLKINLIGHRKRILASLGDR 172
Cdd:cd09500     1 DGNSPASVSEWLDSIGLGDYIETFLKHGYTSMERVKRIWEVELTNVLEINKLGHRKRILASLADR 65

Phosphotyrosine-binding (PTB) PH-like fold; PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to bind peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 312 YKAFYLGSMLIKELRGTESTQDACAKMRANCQKSTEQMKKVptiILSVSYKGVKFIDATNKNIIAEHEIRNISCAAQDPE 391
Cdd:cd00934     3 FQVKYLGSVEVGSSRGVDVVEEALKALAAALKSSKRKPGPV---LLEVSSKGVKLLDLDTKELLLRHPLHRISYCGRDPD 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1953297527 392 DLSTFAYITKDLKSNHHYCHVFTAFDVNLAYEIILTLGQAF 432
Cdd:cd00934    80 NPNVFAFIAGEEGGSGFRCHVFQCEDEEEAEEILQAIGQAF 120

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1953297527   34 PRCPVQTVGQWLESIGLPQYENHLMANGFDNVQFMgsNVMEDQDLLEIGILNSGHRQRILQAIQLL 99
Cdd:smart00454   2 SQWSPESVADWLESIGLEQYADNFRKNGIDGALLL--LLTSEEDLKELGITKLGHRKKILKAIQKL 65

Phosphotyrosine interaction domain (PTB/PID);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 312 YKAFYLGSMLIKELR------GTESTQDA--CAKMRANCQKSTEQMKKVP--TIILSVSYKGVKFIDATNKNIIAEHEIR 381
Cdd:pfam00640   1 FAVRYLGSVEVPEERapdkntRMQQAREAirRVKAAKINKIRGLSGETGPgtKVDLFISTDGLKLLNPDTQELIHDHPLV 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1953297527 382 NIS-CAAQDPEDLSTFAYITKDLKSNHHYCHVFTAFDvnLAYEIILTLGQAFEVA 435
Cdd:pfam00640  81 SISfCADGDPDLMRYFAYIARDKATNKFACHVFESED--GAQDIAQSIGQAFALA 133

Low Density Lipoprotein Receptor Adaptor Protein 1 (LDLRAP1) in mammals and similar proteins Phosphotyrosine-binding (PTB) PH-like fold; The null mutations in the LDL receptor adaptor protein 1 (LDLRAP1) gene, which serves as an adaptor for LDLR endocytosis in the liver, causes autosomal recessive hypercholesterolemia (ARH). LDLRAP1 contains a single PTB domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd contains mammals, insects, and sponges.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 312 YKAFYLGSMLIKELRGTESTQDACAKMRAnCQKSTEqmKKVPTIILSVSYKGVKFIDATNKNIIAEHEIRNIS-CAAqDP 390
Cdd:cd13159     5 FYLKYLGSTLVEKPKGEGATAEAVKTIIA-MAKASG--KKLQKVTLTVSPKGIKVTDSATNETILEVSIYRISyCTA-DA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1953297527 391 EDLSTFAYITKDLKSNHHYCHVFTAFDVNLAYEIILTLGQAFE 433
Cdd:cd13159    81 NHDKVFAFIATNQDNEKLECHAFLCAKRKMAQAVTLTVAQAFN 123

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1953297527  108 DGYHPTSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEvELINVLKINLIGHRKRILASL 169
Cdd:smart00454   2 SQWSPESVADWLESIGLEQYADNFRKNGIDGALLLLLTSE-EDLKELGITKLGHRKKILKAI 62

Shc-like phosphotyrosine-binding (PTB) domain; Shc is a substrate for receptor tyrosine kinases, which can interact with phosphoproteins at NPXY motifs. Shc contains an PTB domain followed by an SH2 domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Shc-like subgroup.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 354 TIILSVSYKGVKFIDATNKNIIAEHEIRNISCAA-QDPEDLSTFAYITKDlKSNHHYCHVFTAFDvNLAYEIILTLGQAF 432
Cdd:cd01209    84 NISLTISTDGLNLVTPDTGQIIANHHMQSISFASgGDPDTYDYVAYVAKD-PVNQRACHVLECGD-GLAQDVIATIGQAF 161

                  ....*....
gi 1953297527 433 EVAYQLALQ 441
Cdd:cd01209   162 ELRFKQYLK 170

SAM domain (Sterile alpha motif);

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1953297527  38 VQTVGQWLESIGLPQYENHLMANGFDNVQFMgsNVMEDQDLLEIGILNSGHRQRILQAIQLL 99
Cdd:pfam07647   6 LESVADWLRSIGLEQYTDNFRDQGITGAELL--LRLTLEDLKRLGITSVGHRRKILKKIQEL 65

SAM domain of EPH-A5 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A5 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A5 receptors and appears to mediate cell-cell initiated signal transduction. Eph-A5 gene is almost exclusively expressed in the nervous system. Murine EPH-A5 receptors participate in axon guidance during embryogenesis and play a role in the adult synaptic plasticity, particularly in neuron-target interactions in multiple neural circuits. Additionally EPH-A5 receptors and its ligand ephrin A5 regulate dopaminergic axon outgrowth and influence the formation of the midbrain dopaminergic pathways. EphA5 gene expression was found decreased in a few different breast cancer cell lines, thus it might be a potential molecular marker for breast cancer carcinogenesis and progression.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1953297527 114 SVAEWLDSIELGDYTKAFLINGYTSMDLLKKIwEVELINVLKINLIGHRKRILASL 169
Cdd:cd09546     5 SVGEWLEAIKMGRYTEIFMENGYSSMDAVAQV-TLEDLRRLGVTLVGHQKKIMNSI 59

Disabled (Dab) Phosphotyrosine-binding domain; Dab is a cystosolic adaptor protein, which binds to the cytoplasmic tails of lipoprotein receptors, such as ApoER2 and VLDLR, via its PTB domain. The dab PTB domain has a preference for unphosphorylated tyrosine within an NPxY motif. Additionally, the Dab PTB domain, which is structurally similar to PH domains, binds to phosphatidlyinositol phosphate 4,5 bisphosphate in a manner characteristic of phosphoinositide binding PH domains. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 311 DYKAFYLGSMLIKELRGTESTQDACAKMRaNCQKSTEQMKKvpTIILSVSYKGVKFIDATNKNIIAEHEIRNISCAAQDP 390
Cdd:cd01215    17 RFKAKLIGIDEVPAARGDKMCQDAMMKLK-GAVKAAGEHKQ--RIWLNISLEGIKILDEKTGALLHHHPVHKISFIARDT 93

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1953297527 391 EDLSTFAYITKdLKSNHHYCHVFTAfdvNLAYEIILTLGQAFEVAYQL 438
Cdd:cd01215    94 TDNRAFGYVCG-LDGGHRFFAIKTA---KAAEPVVLDLRDLFQVVFEL 137

SAM domain of EPH family of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH (erythropoietin-producing hepatocyte) family of receptor tyrosine kinases is a C-terminal signal transduction module located in the cytoplasmic region of these receptors. SAM appears to mediate cell-cell initiated signal transduction via binding proteins to a conserved tyrosine that is phosphorylated. In some cases the SAM domain mediates homodimerization/oligomerization and plays a role in the clustering process necessary for signaling. EPH kinases are the largest family of receptor tyrosine kinases. They are classified into two groups based on their abilities to bind ephrin-A and ephrin-B ligands. The EPH receptors are involved in regulation of cell movement, shape, and attachment during embryonic development; they control cell-cell interactions in the vascular, nervous, epithelial, and immune systems, and in many tumors. They are potential molecular markers for cancer diagnostics and potential targets for cancer therapy.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1953297527  37 PVQTVGQWLESIGLPQYENHLMANGFDNvqfMGSNV-MEDQDLLEIGILNSGHRQRILQAIQLL 99
Cdd:cd09488     1 AFRSVGEWLESIKMGRYKENFTAAGYTS---LDAVAqMTAEDLTRLGVTLVGHQKKILNSIQAL 61

Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (CAPON) Phosphotyrosine-binding (PTB) domain; CAPON (also known as Nitric oxide synthase 1 adaptor protein, NOS1AP, encodes a cytosolic protein that binds to the signaling molecule, neuronal NOS (nNOS). It contains a N-terminal PTB domain that binds to the small monomeric G protein, Dexras1 and a C-terminal PDZ-binding domain that mediates interactions with nNOS. Included in this cd are C. elegan proteins dystrobrevin, DYB-1, which controls neurotransmitter release and muscle Ca(2+) transients by localizing BK channels and DYstrophin-like phenotype and CAPON related,DYC-1, which is functionally related to dystrophin homolog, DYS-1. Mutations in the dystrophin gene causes Duchenne muscular dystrophy. DYS-1 shares sequence similarity, including key motifs, with their mammalian counterparts. These CAPON-like proteins all have a single PTB domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 301 HPEKLIFQSCDYKAFYLGSMLIKelRGTeSTQDACAKMRA---NCQKSTEQMKKVpTIILSVSykGVKFI---------- 367
Cdd:cd01270    20 HNEEAFQHGITFQAKYIGSLEVP--RPS-SRVEIVAAMRRiryEFKAKNIKKKKV-TITVSVD--GVKVVlrkkkkkkgw 93

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 368 -DATNKNIIAEHEIRNISCAAQDPEDLSTFAYITKDLKSNHHYCHVFTAFDVNLAYEIILTLGQAFEVAYQLALQARKGG 446
Cdd:cd01270    94 tWDESKLLLMQHPIYRIFYVSHDSQDLKIFSYIARDGSSNVFKCNVFKSKKKSQAMRIVRTIGQAFEVCHKLSLQHMQGN 173

                  .
gi 1953297527 447 H 447
Cdd:cd01270   174 A 174

SAM domain (Sterile alpha motif);

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1953297527 114 SVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELINvLKINLIGHRKRILASLGD 171
Cdd:pfam07647   8 SVADWLRSIGLEQYTDNFRDQGITGAELLLRLTLEDLKR-LGITSVGHRRKILKKIQE 64

SAM domain of EPH-A2 family of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A2 subfamily of receptor tyrosine kinases is a C-terminal protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A2 receptors and appears to mediate cell-cell initiated signal transduction. For example, SAM domain of EPH-A2 receptors interacts with SAM domain of Ship2 proteins (SH2 containing phosphoinositide 5-phosphotase-2) forming heterodimers; such recruitment of Ship2 by EPH-A2 attenuates the positive signal for receptor endocytosis. Eph-A2 is found overexpressed in many types of human cancer, including breast, prostate, lung and colon cancer. High level of expression could induce cancer progression by a variety of mechanisms and could be used as a novel tag for cancer immunotherapy. EPH-A2 receptors are attractive targets for drag design.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1953297527 108 DGYHPTSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIwEVELINVLKINLIGHRKRILASL 169
Cdd:cd09543     1 EGVPFRTVAEWLESIKMQQYTEHFMAAGYNSIDKVLQM-TQEDIKHIGVRLPGHQKRIAYSI 61

SAM domain of Samd5 subfamily; SAM (sterile alpha motif) domain of Samd5 subfamily is a putative protein-protein interaction domain. Proteins of this subfamily have a SAM domain at the N-terminus. SAM is a widespread domain in signaling and regulatory proteins. In many cases SAM mediates dimerization/oligomerization. The exact function of proteins belonging to this subfamily is unknown.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527  40 TVGQWLESIGLPQYENHLMANGFDNVQFmgSNVMEDQDLLEIGILNSGHRQRILQAIQLL 99
Cdd:cd09527     4 IVYDWLRTLQLEQYAEKFVDNGYDDLEV--CKQIGDPDLDAIGVMNPAHRKRILEAVRRL 61

SAM domain of EPH-B3 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B3 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-B3 receptors and appears to mediate cell-cell initiated signal transduction. EPH-B3 receptor protein kinase performs kinase-dependent and kinase-independent functions. It is known to be involved in thymus morphogenesis, in regulation of cell adhesion and migration. Also EphB3 controls cell positioning and ordered migration in the intestinal epithelium and plays a role in the regulation of adult retinal ganglion cell axon plasticity after optic nerve injury. In some experimental models overexpression of EphB3 enhances cell/cell contacts and suppresses colon tumor growth.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1953297527 113 TSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELINVlKINLIGHRKRILASLGD 171
Cdd:cd09553     7 TTVGDWLDAIKMGRYKENFVSAGFASFDLVAQMTAEDLLRI-GVTLAGHQKKILSSIQD 64

SAM domain of caskin protein repeat 2; SAM (sterile alpha motif) domain repeat 2 of caskin1,2 proteins is a protein-protein interaction domain. Caskin has two tandem SAM domains. Caskin protein is known to interact with membrane-associated guanylate kinase CASK, and may play a role in neural development, synaptic protein targeting, and regulation of gene expression.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1953297527  40 TVGQWLESIGLPQYENHLMANGFDNVQFMGSNVMEdqDLLEIGILNSGHRQRILQAI 96
Cdd:cd09498     9 DLLEWLSLLGLPQYHKVLVENGYDSIDFVTDLTWE--DLQDIGITKLGHQKKLMLAI 63

SAM domain of EPH-B4 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B4 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-B4 receptors and appears to mediate cell-cell initiated signal transduction. EPH-B4 protein kinase performs kinase-dependent and kinase-independent functions. These receptors play a role in the regular vascular system development during embryogenesis. They were found overexpressed in a variety of cancers, including carcinoma of the head and neck, ovarian cancer, bladder cancer, and downregulated in bone myeloma. Thus, EphB4 is a potential biomarker and a target for drug design.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1953297527  40 TVGQWLESIGLPQYENHLMANGFDNVQFMgSNVmEDQDLLEIGILNSGHRQRILQAIQ 97
Cdd:cd09554     5 SVGEWLRAIKMERYEDSFLQAGFTTFQLV-SQI-STEDLLRMGVTLAGHQKKILSSIQ 60

SAM domain of EPH-B1 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B1 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH- B1 receptors. In human vascular endothelial cells it appears to mediate cell-cell initiated signal transduction via the binding of the adaptor protein GRB10 (growth factor) through its SH2 domain to a conserved tyrosine that is phosphorylated. EPH-B1 receptors play a role in neurogenesis, in particular in regulation of proliferation and migration of neural progenitors in the hippocampus and in corneal neovascularization; they are involved in converting the crossed retinal projection to ipsilateral retinal projection. They may be potential targets in angiogenesis-related disorders.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1953297527 113 TSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELINVlKINLIGHRKRILASL 169
Cdd:cd09551     7 TSVEDWLSAIKMSQYRDNFLSSGFTSLQLVAQMTSEDLLRI-GVTLAGHQKKILNSI 62

SAM domain of EPH-B2 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B2 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-B2 receptors and appears to mediate cell-cell initiated signal transduction. SAM domains of this subfamily form homodimers/oligomers (in head-to-head/tail-to-tail orientation); apparently such clustering is necessary for signaling. EPH-B2 receptor is involved in regulation of synaptic function; it is needed for normal vestibular function, proper formation of anterior commissure, control of cell positioning, and ordered migration in the intestinal epithelium. EPH-B2 plays a tumor suppressor role in colorectal cancer. It was found to be downregulated in gastric cancer and thus may be a negative biomarker for it.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1953297527 113 TSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIwEVELINVLKINLIGHRKRILASL 169
Cdd:cd09552     7 STVDEWLDAIKMGQYKESFANAGFTSFDVVSQM-TMEDILRVGVTLAGHQKKILNSI 62

SAM domain of EPH-A10 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A10 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A10 receptors and appears to mediate cell-cell initiated signal transduction. It was found preferentially expressed in the testis. EphA10 may be involved in the pathogenesis and development of prostate carcinoma and lymphocytic leukemia. It is a potential molecular marker and/or therapy target for these types of cancers.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527  40 TVGQWLESIGLPQYENHLMANGFDNVQFMGSnvMEDQDLLEIGILNSGHRQRILQAIQLL 99
Cdd:cd09549     9 SVGEWLEALDLCRYKDNFAAAGYGSLEAVAR--MTAQDVLSLGITSLEHQELLLAGIQAL 66

SAM domain of EPH-A1 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A1 subfamily of the receptor tyrosine kinases is a C-terminal protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A1 receptors and appears to mediate cell-cell initiated signal transduction. Activation of these receptors leads to inhibition of cell spreading and migration in a RhoA-ROCK-dependent manner. EPH-A1 receptors are known to bind ILK (integrin-linked kinase) which is the mediator of interactions between integrin and the actin cytoskeleton. However SAM is not sufficient for this interaction; it rather plays an ancillary role. SAM domains of Eph-A1 receptors do not form homo/hetero dimers/oligomers. EphA1 gene was found expressed widely in differentiated epithelial cells. In a number of different malignant tumors EphA1 genes are downregulated. In breast carcinoma the downregulation is associated with invasive behavior of the cell.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1953297527  37 PVQTVGQWLESIGLPQYENHLMANGFDNVQFMGSnvMEDQDLLEIGILNSGHRQRILQAIQ 97
Cdd:cd09542     3 PYRSVSEWLESIRMKRYILHFRSAGLDTMECVLE--LTAEDLTQMGITLPGHQKRILCSIQ 61

SAM domain of diacylglycerol kinase delta and eta subunits; SAM (sterile alpha motif) domain of DGK-eta-delta subfamily proteins is a protein-protein interaction domain. Proteins of this subfamily are multidomain diacylglycerol kinases with a SAM domain located at the C-terminus. DGK proteins participate in signal transduction. They regulate the level of second messengers such as diacylglycerol and phosphatidic acid. The SAM domain of DGK proteins can form high molecular weight homooligomers through head-to-tail interactions as well as heterooligomers between the SAM domains of DGK delta and eta proteins. The oligomerization plays a role in the regulation of DGK intracellular localization.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1953297527  38 VQTVGQWLESIGLPQYENHLMANGFDNVQFMGsnvMEDQDLLEIGILNSGHRQRILQAIQLL 99
Cdd:cd09507     7 TEEVGAWLESLQLGEYRDIFARNDIRGSELLH---LERRDLKDLGITKVGHVKRILQAIKDL 65

SAM domain of Arap1,2,3 (angiotensin receptor-associated protein); SAM (sterile alpha motif) domain of Arap1,2,3 subfamily proteins (angiotensin receptor-associated) is a protein-protein interaction domain. Arap1,2,3 proteins are phosphatidylinositol-3,4,5-trisphosphate-dependent GTPase-activating proteins. They are involved in phosphatidylinositol-3 kinase (PI3K) signaling pathways. In addition to SAM domain, Arap1,2,3 proteins contain ArfGap, PH-like, RhoGAP and UBQ domains. SAM domain of Arap3 protein was shown to interact with SAM domain of Ship2 phosphatidylinositol-trisphosphate phosphatase proteins. Such interaction apparently plays a role in inhibition of PI3K regulated pathways since Ship2 converts PI(3,4,5)P3 into PI(3,4)P2. Proteins of this subfamily participate in regulation of signaling and trafficking associated with a number of different receptors (including EGFR, TRAIL-R1/DR4, TRAIL-R2/DR5) in normal and cancer cells; they are involved in regulation of actin cytoskeleton remodeling, cell spreading and formation of lamellipodia.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1953297527 113 TSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELiNVLKINLIGHRKRILASL 169
Cdd:cd09490     4 LDIAEWLASIHLEQYLDLFREHGYVTATDCQGINDSRL-KQIGISPTGHRRRILKQL 59

uncharacterized protein LOC417372 Phosphotyrosine-binding (PTB) PH-like fold; The function of LOC417372 and its related proteins are unknown to date. Members here contain a N-terminal RUN domain, followed by a PDZ domain, and a C-terminal PTB domain. The RUN domain is involved in Ras-like GTPase signaling. The PDZ domain (also called DHR/Dlg homologous region or GLGF after its conserved sequence motif) binds C-terminal polypeptides, internal (non-C-terminal) polypeptides, and lipids. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 312 YKAFYLGSMLIKELRGTESTQDAcaKMRANCQKSTEQmKKVPTIILSVsykGVKFIDATNKNIIAEHEIRNISCAAQDPE 391
Cdd:cd13168     3 YKALYLGQVEVGEDGGVEQIESA--AIIVVLESDLTP-KEVLLELGEI---GVTVWDKSTSEVLFKHSFPEISSCGRRVD 76

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1953297527 392 DLSTFAYITKDL---KSNHHYCHVFTAFDVNLAYEIILTLGQAF 432
Cdd:cd13168    77 DPNYFAYIAGDTpcsLAKHFVCYVFEAADEEEAETILQGIAQGF 120

SAM domain of SASH1 proteins, repeat 2; SAM (sterile alpha motif) repeat 2 of SASH1 proteins is a protein-protein interaction domain. Members of this subfamily are putative adaptor proteins. They appear to mediate signal transduction. SASH1 can bind 14-3-3 proteins in response to IGF1/phosphatidylinositol 3-kinase signaling. SASH1 was found upregulated in different tissues including thymus, placenta, lungs and downregulated in some breast tumors, liver metastases and colon cancers if compare to corresponding normal tissues. SASH1 is a potential candidate for a tumor suppressor gene in breast cancers. At the same time, downregulation of SASH1 in colon cancer is associated with metastasis and a poor prognosis.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1953297527  38 VQTVGQWLESIGLPQYENHLMANGFDNVQFMGSnvMEDQDLLEIGILNSGHRQRILQAIQLL 99
Cdd:cd09492     7 VSSVSDWLVSIGLPMYSPPLLEAGFSTLSRVSS--LSETCLREAGITEERHIRKLLSAARLV 66

SAM domain of EPH-A7 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A7 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A7 receptors and appears to mediate cell-cell initiated signal transduction. EphA7 was found expressed in human embryonic stem (ES) cells, neural tissues, kidney vasculature. EphA7 knockout mice show decrease in cortical progenitor cell death at mid-neurogenesis and significant increase in cortical size. EphA7 may be involved in the pathogenesis and development of different cancers; in particular, EphA7 was found upregulated in glioblastoma and downregulated in colorectal cancer and gastric cancer. Thus, it is a potential molecular marker and/or therapy target for these types of cancers.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1953297527  40 TVGQWLESIGLPQYENHLMANGFDNVQFMGSnvMEDQDLLEIGILNSGHRQRILQAIQ 97
Cdd:cd09548     9 SVGEWLEAIKMERYKDNFTAAGYNSLESVAR--MTIEDVMSLGITLVGHQKKIMSSIQ 64

GTPase activating protein for Rab 6 Phosphotyrosine-binding (PTB) domain; GAPCenA is a centrosome-associated GTPase activating protein (GAP) for Rab 6. It consists of an N-terminal PTB domain and a C-terminal TBC domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953297527 316 YLGSMLIKELRGTESTQDACAKMRANCQKSTEqmkkvptIILSV--SYKG-VKFIDATNKNIIAEHEIRNIS-CA--AQD 389
Cdd:cd01211     8 YLGCAKVNAPRSETEALRIMAILREQSAQPIK-------VTLSVpnSSEGsVRLYDPTSNTEIASYPIYRILfCArgPDG 80

                          90       100
                  ....*....|....*....|....
gi 1953297527 390 PEDLSTFAYITKDLKSNHHYCHVF 413
Cdd:cd01211    81 TSESDCFAFTWSHGETAIFQCHVF 104

SAM domain of liprin-beta1,2 proteins repeat 2; SAM (sterile alpha motif) domain repeat 2 of liprin-beta1,2 proteins is a protein-protein interaction domain. Liprin-beta proteins contain three copies (repeats) of SAM domain. They may form heterodimers with liprin-alpha proteins through their SAM domains. It was suggested based on bioinformatic approaches that the second SAM domain of liprin-beta potentially is able to form polymers. Liprins were originally identified as LAR (leukocyte common antigen-related) transmembrane protein-tyrosine phosphatase-interacting proteins. They participate in mammary gland development, in axon guidance, and in the maintenance of lymphatic vessel integrity.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1953297527  41 VGQWLESIGLPQYENHLMANGFDNVQFmgsNVMEDQDLLEIGILNSGHRQRILQAIQLL 99
Cdd:cd09566     7 VLRWLDDIGLPQYKDAFSEAKVDGRML---HYLTVDDLLHLKVTSALHHASIRRGIQVL 62

SAM (Sterile alpha motif ), SASH1-like; SAM (sterile alpha motif) domain of SASH1-like proteins is a protein-protein interaction domain. Members of this subfamily are putative adaptor proteins. They appear to mediate signal transduction. Proteins of this subfamily are known to be involved in preventing DN thymocytes from premature initiation of programmed cell death and in B cells activation and differentiation. They have been found downregulated in some breast tumors, liver metastases and colon cancers if compare to corresponding normal tissues.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1953297527 112 PTSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELINvLKINLIGHRKRILAS 168
Cdd:cd09493     2 PKTVEELLERINLQEHTSTLLLNGYETLEDFKDLKESHLNE-LNITDPEHRAKLLTA 57