Cas scaffolding protein family member 4 is a protein that in humans is encoded by the CASS4 gene.
History and discovery
CASS4 (Crk associated substrate 4) is the fourth and last described member of the CAS protein family. CASS4 was detected by Singh et al. in 2008 following in silico screening of databases describing expressed sequence tags from an evolutionarily diverse group of organisms, using the CAS-related proteins (p130Cas, NEDD9/HEF1 and EFS) mRNAs as templates. Singh et al. subsequently cloned and characterized the CASS4 gene, originally assigning the name HEPL (HEF1-EFS-p130Cas-like) for similarity to the other three defined CAS genes. The official name was subsequently changed to CASS4 by the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC).
Gene
The chromosomal location of the CASS4 gene is 20q13.31, with genomic coordinates of 20: 56411548-56459340 on the forward strand in GRChB38p2. While its HGNC-approved symbol is CASS4, this gene has multiple synonyms, including "HEF-like protein", "HEF1-Efs-p130Cas-like", HEFL, HEPL and C20orf32 ("chromosome 20 open reading frame 32"). Official IDs assigned to this gene include 15878 (HGNC), 57091 (Entrez Gene) and ENSG00000087589 (Ensembl). In humans four transcript variants are known. The first and second each contain 7 exons and encode the same full-length protein isoform a (786 amino acids, considered the major isoform), the third one contains 6 exons and encodes a shorter isoform b (732 amino acids) and the fourth one contains 5 exons and encodes the shortest isoform c (349 amino acids). Cumulatively, the CASS4 transcripts are most highly expressed in spleen and lung among normal tissues, and are highly expressed in ovarian and leukemia cell lines.
To date, little effort has been applied to the direct study of transcriptional regulation of CASS4. The SABiosciences' DECODE database, based on the UCSC Bioinformatics Genome Browser, proposes several transcriptional regulators for CASS4 based on its promoter region sequence: NF-κβ, p53, LCR-F1 (NFE2-L1, nuclear factor, erythroid 2-like1), MAX1, C/EBPα, CHOP-10 (C/EBP homologous protein 10), POU3F1 (POU domain, class 3, transcription factor 1, aka Oct-6), Areb6 (ZEB1, Zinc finger E-box binding homeobox 1). These are compatible with regulation relevant to lymphocytes and deregulation in cancer.
Protein family
In vertebrates, the CAS protein family contains four members: p130Cas/BCAR1, NEDD9/HEF1, EFS and CASS4. There are no paralogous genes for this family in acoelomates, pseudocoelomates, and nematodes, while a single ancestral member is found in Drosophila. Evolutionary divergence of the CAS proteins family members is discussed by Singh et al. in detail.
Structure
All CAS protein family members have common structural characteristics. CAS proteins have an amino terminal SH3 domain enabling interaction with poly-proline motif-containing proteins such as FAK. Carboxy-terminal to this, they possess an unstructured domain containing multiple SH2 binding site motifs, which when tyrosine-phosphorylated allow interaction with SH2 domain containing proteins. Further to the carboxy-terminus, they have a four-helix bundle rich in serine residues, and a second highly conserved four-helix bundle that has been recognized as functionally and structurally similar to a focal adhesion targeting [FAT] domain. For the better studied members of the CAS family (BCAR1 and NEDD9), all of these domains have been defined as crucial for recognition and binding by other proteins, reflecting the primary role of CAS family proteins as cell signaling cascades mediators.