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enhancer of filamentation 1; HEF1; CRK-associated substrate-related protein; CAS-L; CasL; p105; protein NEDD9; NY-REN-12 antigen (NEDD9)
Function:
1) docking protein
2) tyrosine-kinase-based signaling related to cell adhesion
3) transmits growth control signals between focal adhesions at the cell periphery & mitotic spindle in response to adhesion or growth stimulation
4) 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
5) interacts with BCAR3, SH2D3C, MICAL, TXNL4
6) can heterodimerize with HLH proteins ID2, E12, E47, p130cas
7) forms complexes with related:
a) adhesion focal tyrosine kinase (RAFTK)
b) adapter protein CRKL
c) LYN kinase
8) activated upon induction of cell growth
9) phosphorylated by Focal adhesion kinase 1 (FAK1) at the YDYVHL motif & subsequently by SRC family kinases (FYN, SRC, LCK, CRK)
10) cell cycle-regulated processing produces four isoforms:
a) p115, p105, p65, & p55
b) isoform p115 arises from p105 phosphorylation & appears later in the cell cycle
c) isoform p55 arises from p105 as a result of cleavage at a caspase cleavage-related site & it appears specifically at mitos
d) the p65 isoform is poorly detected
11) Tyr phosphorylation occurs upon stimulation of G-protein coupled C1a calcitonin receptor
12) calcitonin-stimulated Tyr phosphorylation is mediated by Ca+2- & protein kinase C-dependent mechanisms & requires the actin cytoskeleton
13) phosphorylation at Ser-369 induces proteasomal degradation
14) interacts with BCAR3 & SH2D3C (putative)
15) homodimer
16) can heterodimerize with HLH proteins ID2, E12, E47 & with p130cas
17) forms complexes in vivo with RAFTK, adapter protein CRKL & LYN kinase
18) 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)
General
docking protein
phosphoprotein
Properties
SIZE: MW = 93 kD
entity length = 834 aa
COMPARTMENT: cytoplasm
cell nucleus
golgi
MOTIF: src homology 3 [SH3] domain
SITE: 3-65
MOTIF: Tyr phosphorylation site {Y12}
Tyr phosphorylation site {Y92}
D1M1 interaction {102-229}
MOTIF: Tyr phosphorylation site {Y166}
Tyr phosphorylation site {Y177}
Tyr phosphorylation site {Y189}
Tyr phosphorylation site {Y214}
Tyr phosphorylation site {Y223}
Tyr phosphorylation site {Y241}
Tyr phosphorylation site {Y261}
Ser phosphorylation site {S296}
Tyr phosphorylation site {Y317}
Tyr phosphorylation site {Y345}
proteolytic site {360-363}
Ser phosphorylation site {S369}
helix-loop-helix
NAME: helix-loop-helix
SITE: 710-760
FOR-BINDING-VIA: helix-loop-helix
Database Correlations
OMIM 602265
UniProt Q14511
PFAM correlations
Entrez Gene 4739
Kegg hsa:4739
References
UniProt :accession Q14511