cbl proto-oncogene protein (E3 ubiquitin-protein ligase CBL, signal transduction protein CBL, proto-oncogene c-CBL, Casitas B-lineage lymphoma proto-oncogene protein, RING finger protein 55, BL, CBL2, RNF55)

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Function

role in signal transduction in hematopoietic cells
adapter protein that functions as a negative regulator of many signaling pathways that start from receptors at the cell surface
acts as an E3 ubiquitin-protein ligase
recognizes activated receptor tyrosine kinases, including PDGFA, EGF & CSF1, & terminates signaling
associates with NCK via its SH3 domain
phosphorylated C-terminus interacts with CD2AP via its 2nd SH3 domain
binds to UBE2L3
interacts with adapters SLA, SLA2 & with the phosphorylated C-terminus of SH2B2
interacts with EGFR, SYK & ZAP70 via the highly conserved Cbl-N region
interacts with SORBS1 & INPPL1/SHIP2
interacts with phosphorylated LAT2
may interact with CBLB (putative)
protein modification; protein ubiquitination
phosphorylated on Tyr by EGFR, SYK, FYN & ZAP70 (putative)
phosphorylated on Tyr by INSR

RING-type Zn+2 finger domain mediates binding to an E2 ubiquitin-conjugating enzyme
N-terminus contains
- PTB domain
  - contains 3 different subdomains:
  - a four-helix bundle (4H)
  - Ca+2-binding EF hand
  - divergent SH2 domain
- short linker region
- RING-type Zn+2 finger
contains 1 CBL N-terminal domain
contains 2 EF-hand-like domains
- has 1 functional Ca+2-binding site
contains 1 RING-type Zn+2 finger
contains 1 SH2 domain
contains 1 UBA domain

defects in CBL are the cause of Noonan syndrome-like disorder
can be converted to an oncogenic protein by deletions or mutations that disturb its ability to down-regulate receptor tyrosine kinases