enhancer of filamentation 1; HEF1; CRK-associated substrate-related protein; CAS-L; CasL; p105; protein NEDD9; NY-REN-12 antigen (NEDD9)

Function

• docking protein
• tyrosine-kinase-based signaling related to cell adhesion
• transmits growth control signals between focal adhesions at the cell periphery & mitotic spindle in response to adhesion or growth stimulation
• integrin beta-1 or B-cell antigen receptor mediated signaling in B-cells & T-cells
  • integrin beta-1 stimulation leads to recruitment of CRK, NCK & SHPTP2 to the phospho-Tyr form
• interacts with BCAR3, SH2D3C, MICAL, TXNL4
• can heterodimerize with HLH proteins ID2, E12, E47, p130cas
• forms complexes with related:
  • adhesion focal tyrosine kinase (RAFTK)
  • adapter protein CRKL
  • LYN kinase
• activated upon induction of cell growth
• phosphorylated by Focal adhesion kinase 1 (FAK1) at the YDYVHL motif & subsequently by SRC family kinases (FYN, SRC, LCK, CRK)
• cell cycle-regulated processing produces four isoforms:
  • p115, p105, p65, & p55
  • isoform p115 arises from p105 phosphorylation & appears later in the cell cycle
  • isoform p55 arises from p105 as a result of cleavage at a caspase cleavage-related site & it appears specifically at mitos
  • the p65 isoform is poorly detected
• Tyr phosphorylation occurs upon stimulation of G-protein coupled C1a calcitonin receptor
• calcitonin-stimulated Tyr phosphorylation is mediated by Ca+2- & protein kinase C-dependent mechanisms & requires the actin cytoskeleton
• phosphorylation at Ser-369 induces proteasomal degradation
• interacts with BCAR3 & SH2D3C (putative)
• homodimer
• can heterodimerize with HLH proteins ID2, E12, E47 & with p130cas
• forms complexes in vivo with RAFTK, adapter protein CRKL & LYN kinase
• interacts with MICAL & TXNL4/DIM1

Structure

• contains a central domain containing multiple potential SH2-binding sites & a C-terminal domain containing a divergent helix-loop-helix (HLH) motif
• the SH2-binding sites putatively bind CRK, NCK & ABL SH2 domains
• the HLH motif confers specific interaction with the HLH proteins ID2, E12 & E47
  • required for induction of pseudohyphal growth in yeast
  • mediates homodimerization & heterodimerization with p130cas
• the SH3 domain interacts with two proline-rich regions of PTK2/FAK1
• belongs to the CAS family
• contains 1 SH3 domain

Compartment

• cytoplasm, cell cortex, nucleus, Golgi
• cell projection, lamellipodium
• cell junction, focal adhesion
• localizes to both the cell nucleus & the cell periphery & is differently localized in fibroblasts & epithelial cells
• in fibroblasts is predominantly nuclear & in some cells is present in the Golgi
• in epithelial cells, localized predominantly in the cell periphery with particular concentration in lamellipodia but is also found in the nucleus
• isoforms p105 & p115 are predominantly cytoplasmic & associate with focal adhesions
• p55 associates with the mitotic spindle

Alternative splicing

named isoforms=2

Expression

• widely expressed.
• expressed in kidney, lung, placenta > T-cells, B-cells

Pathology

• pathways leading to progression of cancer (putative)

More general terms

• docking protein
• phosphoprotein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4739
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:4739
• OMIM: https://mirror.omim.org/entry/602265
• UniProt: http://www.uniprot.org/uniprot/Q14511.html