Human SHC4 locus spans 139,707 bases on chromosome 15, starting at position 46,903,227 bp and ending at position 47,042,933 from pter (according to hg18-Mar-2006). The same locus that codifies for SHC4 transcript also produces the small and unrelated protein EP300 interacting inhibitor of differentiation 1 (EID1) that has been found only in the mammalian genome. Orthologs of SHC4 are present in other metazoan. The corresponding mouse gene is located on chromosome 2F1.

Both human and mouse SHC4 open reading frame consist of twelve exons, producing nucleotide sequences of 1893 nt and 1881 nt respectively that encode for putative polypeptides of 630 amino acids in human and 626 amino acids in mouse. No clear evidence of alternative splicing isoforms of the main mRNA transcript has been found so far.

None identified.

The amino-terminal positioning of the phosphotyrosine-binding (PTB) domain and the carbossi-terminal positioning of the Src homology 2 (SH2) domain is a hallmark of the SHC family. These two domains are divided by the CH1 region, which contains three highly conserved tyrosine residues. A second collagen homology (CH2) region is present in the longest isoforms of the Shc family members and in SHC4. The human SHC4 protein consists of 630 amino acids with a total estimated molecular weight of 69 KDa. Although no splicing isoform are known, it is postulated that two other polypeptides may be produced by the usage of alternate initiator codons, corresponding to predicted products of 59 KDa and 49 KDa.

Human SHC4 shows a specific expression in advanced-stage melanomas and in no other human normal and tumoral adult tissues. SHC4 protein product is detected in primary cultures and cell lines of metastatic melanoma, while its expression decreases in non-invasive melanoma cell lines and in primary melanocytes. In adult mouse tissues SHC4 is primarily detected in brain and skeletal muscle.

In humans, SHC4 protein is mostly localized in the cytosol of melanocytes and melanoma cells and partly to cell membranes. The murine SHC4 protein was demonstrated to co-localize with muscle-specific kinase (MuSK) at the postsynaptic neuromuscular junction (NMJ).

SHC4 is a substrate of several receptor tyrosine kinases (RTK) and G protein-coupled receptors (GPCR). When ectopically expressed in non-metastatic melanoma cell lines SHC4 becomes phosphorylated upon growth factor stimulation and associates with the growth factor receptor-bound protein 2 (Grb2). Tyrosine-phosphorylated SHC4 induces Ras GTPase and mitogen activated protein kinase (MAPK) activation, resulting in enhanced cell migration. Conversely, silencing of SHC4 expression in metastatic melanoma cells reduces migration without affecting MAPK pathway, suggesting that SHC4 may participate in both Ras - dependent and - independent pathways in human melanoma. SHC4 appears to be important for the regulation of postsynaptic signals of motoneurons through association with MuSK and activation of acetylcholine receptors (AChR), as indicated by biochemical studies of the mouse protein.

Among all the human paralogous genes, SHC4 shares an overall identity at protein level of 45%, 37% and 41% with SHC1, SHC2, and SHC3 respectively. The highest conservation is detected in the PTB and SH2 regions. Human and murine SHC4 display 75% sequence identity in both the PTB and SH2 domains.