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 348561211    4 NIVYEWLKALQLPQYAESFVdNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRRLR 63
Cdd:pfam00536   6 EDVGEWLESIGLGQYIDSFR-AGYIDGDALLQLTEDDLLKLGVTLLGHRKKILYAIQRLK 64

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 348561211    4 NIVYEWLKALQLPQYAESFVdNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRRLR 63
Cdd:pfam00536   6 EDVGEWLESIGLGQYIDSFR-AGYIDGDALLQLTEDDLLKLGVTLLGHRKKILYAIQRLK 64

SAM domain of Ship2 lipid phosphatase proteins; SAM (sterile alpha motif) domain of Ship2 subfamily is a protein-protein interaction domain. Ship2 proteins are lipid phosphatases (Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2) containing an N-terminal SH2 domain, a central phosphatase domain and a C-terminal SAM domain. Ship2 is involved in a number of PI3K signaling pathways. For example, it plays a role in regulation of the actin cytoskeleton remodeling, in insulin signaling pathways, and in EphA2 receptor endocytosis. SAM domain of Ship2 can interact with SAM domain of other proteins in these pathways, thus participating in signal transduction. In particular, SAM of Ship2 is known to form heterodimers with SAM domain of Eph-A2 receptor tyrosine kinase during receptor endocytosis as well as with SAM domain of PI3K effector protein Arap3 in the actin cytoskeleton signaling network. Since Ship2 plays a role in negatively regulating insulin signaling, it has been suggested that inhibition of its expression or function may contribute in treating type 2 diabetes and obesity-induced insulin resistance.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 348561211   6 VYEWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVR 60
Cdd:cd09491    8 VSEWLMNLGLQQYEEGLMHNGWDSLEFLSDITEEDLEEAGVTNPAHKRRLLDSLQ 62

SAM (Sterile alpha motif ); SAM (Sterile Alpha Motif) domain is a module consisting of approximately 70 amino acids. This domain is found in the Fungi/Metazoa group and in a restricted number of bacteria. Proteins with SAM domains are represented by a wide variety of domain architectures and have different intracellular localization, including nucleus, cytoplasm and membranes. SAM domains have diverse functions. They can interact with proteins, RNAs and membrane lipids, contain site of phosphorylation and/or kinase docking site, and play a role in protein homo and hetero dimerization/oligomerization in processes ranging from signal transduction to regulation of transcription. Mutations in SAM domains have been linked to several diseases.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 348561211   6 VYEWLKALQLPQYAESFVDNgYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRR 61
Cdd:cd09487    2 VAEWLESLGLEQYADLFRKN-EIDGDALLLLTDEDLKELGITSPGHRKKILRAIQR 56

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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 348561211   4 NIVYEWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRRLRE 64
Cdd:cd09498    8 NDLLEWLSLLGLPQYHKVLVENGYDSIDFVTDLTWEDLQDIGITKLGHQKKLMLAIKKLKD 68

SAM domain of caskin protein repeat 1; SAM (sterile alpha motif) domain repeat 1 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 apparently may play a role in neural development, synaptic protein targeting, and regulation of gene expression.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 348561211   5 IVYEWLKALQLPQYAESFVDNGYDDLEVCKqIGDPDLDAIGVLAPAHRRRVLEAVRRLREQD 66
Cdd:cd09497    6 AIFDWLREFGLEEYTPNFIKAGYDLPTISR-MTPEDLTAIGITKPGHRKKLKSEIAQLQIPD 66

SAM domain of EPH-A4 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A4 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A4 receptors and appears to mediate cell-cell initiated signal transduction. SAM domains of EPH-A4 receptors can form homodimers. EPH-A4 receptors bind ligands such as erphirin A1, A4, A5. They are known to interact with a number of different proteins, including meltrin beta metalloprotease, Cdk5, and EFS2alpha, however SAM domain doesn't participate in these interactions. EPH-A4 receptors are involved in regulation of corticospinal tract formation, in pathway controlling voluntary movements, in formation of motor neurons, and in axon guidance (SAM domain is not required for axon guidance or for EPH-A4 kinase signaling). In Xenopus embryos EPH-A4 induces loss of cell adhesion, ventro-lateral protrusions, and severely expanded posterior structures. Mutations in SAM domain conserved tyrosine (Y928F) enhance the ability of EPH-A4 to induce these phenotypes, thus supporting the idea that the SAM domain may negatively regulate some aspects of EPH-A4 activity. EphA4 gene was found overexpressed in a number of different cancers including human gastric cancer, colorectal cancer, and pancreatic ductal adenocarcinoma. It is likely to be a promising molecular target for the cancer therapy.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 348561211   6 VYEWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRRLREQ 65
Cdd:cd09545    6 VDDWLQAIKMERYKDNFTAAGYTTLEAVVHMNQDDLARIGISAIAHQNKILSSVQGMRSQ 65

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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 348561211   6 VYEWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRRLREQ 65
Cdd:cd09551    9 VEDWLSAIKMSQYRDNFLSSGFTSLQLVAQMTSEDLLRIGVTLAGHQKKILNSIQSMRVQ 68

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
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 348561211   6 VYEWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRRL 62
Cdd:cd09488    5 VGEWLESIKMGRYKENFTAAGYTSLDAVAQMTAEDLTRLGVTLVGHQKKILNSIQAL 61

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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 348561211   6 VYEWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRRLREQD 66
Cdd:cd09554    6 VGEWLRAIKMERYEDSFLQAGFTTFQLVSQISTEDLLRMGVTLAGHQKKILSSIQAMGIQN 66

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 348561211   2 CTNIVYEWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRRLREQ 65
Cdd:cd09549    6 SFGSVGEWLEALDLCRYKDNFAAAGYGSLEAVARMTAQDVLSLGITSLEHQELLLAGIQALRAQ 69

SAM domain of EPH-A6 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A6 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A6 receptors and appears to mediate cell-cell initiated signal transduction. Eph-A6 gene is preferentially expressed in the nervous system. EPH-A6 receptors are involved in primate retina vascular and axon guidance, and in neural circuits responsible for learning and memory. EphA6 gene was significantly down regulated in colorectal cancer and in malignant melanomas. It is a potential molecular marker for these cancers.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 348561211   6 VYEWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRRLR 63
Cdd:cd09547    6 VSDWLDSIKMGQYKNNFMAAGFTTLDMVSRMTIDDIRRIGVTLIGHQRRIVSSIQTLR 63

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
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 348561211   6 VYEWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVR 60
Cdd:cd09542    7 VSEWLESIRMKRYILHFRSAGLDTMECVLELTAEDLTQMGITLPGHQKRILCSIQ 61

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 348561211   6 VYEWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAV 59
Cdd:cd09493    5 VEELLERINLQEHTSTLLLNGYETLEDFKDLKESHLNELNITDPEHRAKLLTAA 58

SAM domain of SAMSN1 subfamily; SAM (sterile alpha motif) domain of SAMSN1 (also known as HACS1 or NASH1) proteins is a predicted protein-protein interaction domain. Members of this group are putative signaling/adaptor proteins. They appear to mediate signal transduction in lymphoid tissues. Murine HACS1 protein likely plays a role in B cell activation and differentiation. Potential binding partners of HACS1 are SLAM, DEC205 and PIR-B receptors and also some unidentified tyrosine-phosphorylated proteins. Proteins of this group were found preferentially expressed in normal hematopietic tissues and in some malignancies including lymphoma, myeloid leukemia and myeloma.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 348561211   8 EWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRRLRE 64
Cdd:cd09561   10 ELLERIHLQEYTSTLLLNGYETLEDLKDLKESHLIELNITDPEDRARLLSAAENLLD 66

SAM domain of EPH-B6 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B6 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-B6 receptors and appears to mediate cell-cell initiated signal transduction. Receptors of this type are highly expressed in embryo and adult nervous system, in thymus and also in T-cells. They are involved in regulation of cell adhesion and migration. (EPH-B6 receptor is unusual; it fails to show catalytic activity due to alteration in kinase domain). EPH-B6 may be considered as a biomarker in some types of tumors; EPH-B6 activates MAP kinase signaling in lung adenocarcinoma, suppresses metastasis formation in non-small cell lung cancer, and slows invasiveness in some breast cancer cell lines.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 348561211   2 CTNIVYEWLKALQLPQYAESFVDNGYDDLEVCKQIGDPDLDAIGVLAPAHRRRVLEAVRRLREQ 65
Cdd:cd09555    5 CLDSPQAWLSAIGLECYQDNFSKFGLCTFSDVAQLSLEDLPALGITLAGHQKKLLHHIQLLQQH 68

SAM domain of VTS1 RNA-binding proteins; SAM (sterile alpha motif) domain of VTS1 subfamily proteins is RNA binding domain located in the C-terminal region. SAM interacts with stem-loop structures of mRNA. Proteins of this subfamily participate in regulation of transcript stability and degradation, and also may be involved in vacuolar protein transport regulation. VTS1 protein of S.cerevisiae induces mRNA degradation via the major deadenylation-dependent mRNA decay pathway; VTS1 recruits CCR4/POP2/NOT deadenylase complex to target mRNA. The recruitment is the initial step resulting in poly(A) tail removal transcripts. Potentially SAM domain may be responsible not only for RNA binding but also for deadenylase binding.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 348561211   9 WLKALQLPQYAESFVDNGYDDLevcKQIGDPDLDAIGVLAPAHRRRVLEAVRRLRE 64
Cdd:cd09556   12 WLRSLRLHKYTDNLKDLSWKEL---IELDDEDLEDKGVSALGARRKLLKAFEIVRE 64

SAM domain of Shank1,2,3 family proteins; SAM (sterile alpha motif) domain of Shank1,2,3 family proteins is a protein-protein interaction domain. Shank1,2,3 proteins are scaffold proteins that are known to interact with a variety of cytoplasmic and membrane proteins. SAM domains of the Shank1,2,3 family are prone to homooligomerization. They are highly enriched in the postsynaptic density, acting as scaffolds to organize assembly of postsynaptic proteins. SAM domains of Shank3 proteins can form large sheets of helical fibers. Shank genes show distinct patterns of expression, in rat Shank1 mRNA is found almost exclusively in brain, Shank2 in brain, kidney and liver, and Shank3 in heart, brain and spleen.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 348561211   6 VYEWLKALQLPQYAESFVDNGYDDLEVcKQIGDPDLDAIGVLAPAHRRRVLEAVRRL 62
Cdd:cd09506   10 VGDWLESLNLGEHRERFMDNEIDGSHL-PNLDKEDLTELGVTRVGHRMNIERALKKL 65

SAM domain of TNK(ACK)-like non-receptor tyrosine-protein kinases; SAM (sterile alpha motif) domain of TNK-like subfamily is a putative protein-protein interaction domain. This subfamily includes TNK1 and TNK2 (also known as ACK1) non-receptor tyrosine-protein kinases. They contain a SAM domain at the N-terminus followed by a catalytic domain and a few other domains. Members of this group are involved in the regulation of cell adhesion and growth, receptor degradation, and axonal guidance. Deletion of the SAM domain resulted in reduction of Ack1 ability to undergo autophosphorylation and dramatically reduces ubiquitination of Ack1 catalyzed by HECT E3 ubiquitin ligase (Nedd4-1) during EGF-induced Ack1 degradation. It has been suggested that the lysine-rich region in SAM domain might be a major ubiquitination site. Members of this group are also associated with some cancers. Amplification of the Ack1 gene correlates with prostate and lung cancer progression, and Ack1 overexpression increases invasiveness. Oncogenecity of Tnk1 gene apparently depends on cell context; it may play a role in tumor suppression since Tnk1 knockout mice can develop spontaneous tumors.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 348561211   6 VYEWLKALQLPQYAESFVDngydDLEVC-----KQIGDPDLDAIGVLAPAhRRRVLEAVRRLR 63
Cdd:cd09539    5 LYEFLREAQLQQFYSRIRD----DLKVTrlshfKYVKEEDLEKIGMSKPE-QRRLREAVKKYK 62

SAM domain of Smaug subfamily; SAM (sterile alpha motif) domain of Smaug proteins is an RNA recognition domain. It binds a specific RNA motif known as Smaug recognition element (SRE). Among members of this group are invertebrate Smaug (Smg) proteins and vertebrate Smaug1 and Smaug2 proteins. They are involved in post-transcriptional control during early embryogenesis in animals. In Drosophila, Smaug protein is a translational repressor of mRNA of Nanos (Nos) protein. Gradient of Nanos is required for proper abdominal segmentation. SAM domain interacts specifically with the Nanos mRNA regulatory regions. Moreover, Smaug protein is involved in regulation of specific maternal transcripts degradation in Drosophila early embryo via recruitment of the CCR4/POP2/NOT deadenylase.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 348561211   9 WLKALQLPQYAESFVDNGYDDLevcKQIGDPDLDAIGVLAPAhRRRVLEAVRRLRE 64
Cdd:cd09557   12 WLKSLRLHKYASLFSQMTYEEM---LNLTEEQLEAQGVTKGA-RHKIALSIQKLKE 63