RTK SLAP DOWN: The emerging role of Src-like adaptor protein as a key player in receptor tyrosine kinase signaling

Skb5, an SH3 adaptor protein, regulates Pmk1 MAPK signaling by controlling the intracellular localization of Mkh1 MAPKKK

“…SLAP has been shown to interact with a subset of RTKs including Eph receptors and PDGFRs. (Wybenga-Groot and McGlade, 2015). Interestingly, SLAP function in the regulation of TCR and RTK signaling is closely coupled with its binding to the ubiquitin ligase Cbl through its C-terminal region, allowing for ubiquitylation of substrates such as EphA2 and its subsequent degradation (Wybenga-Groot and McGlade, 2015).…”

“…(Wybenga-Groot and McGlade, 2015). Interestingly, SLAP function in the regulation of TCR and RTK signaling is closely coupled with its binding to the ubiquitin ligase Cbl through its C-terminal region, allowing for ubiquitylation of substrates such as EphA2 and its subsequent degradation (Wybenga-Groot and McGlade, 2015). This prompted us to investigate the protein amount of Mkh1 in the absence and presence of Skb5 overproduction, with a presumption that Skb5 might couple Mkh1 to the ubiquitin-mediated degradation.…”

SLAP2 adaptor binding disrupts c-CBL autoinhibition to activate ubiquitin ligase function

“…Outside the hematopoietic system, SLAP is important for down regulation of SRC and EPHA2 signaling in intestinal epithelial cells as well as PDGFR signaling induced dorsal ruffle formation 46-48 . SLAP and SLAP2 are membrane associated proteins by virtue of an amino-terminal myristoylation site. They contain adjacent SH3 and SH2 domains most closely related to those found in SRC family kinase HCK, followed by a carboxy (C)-terminal tail region lacking obvious domains or protein interaction motifs 33,43,[49][50][51] . The SLAP2 SH3/SH2 domains adopt typical folds with a uniquely short connector sequence that positions them in close association consistent with a functional unit that binds proteins through tandem association 51,52 .…”

“…Slap/Slap2 deficient mice also show defective down regulation of Granulocyte/macrophage colonystimulating factor receptor (GM-CSFR) signaling leading to a block in normal dendritic cell development 40 , as well as enhanced platelet activation signaling and arterial thrombus formation 41 . In addition, SLAP/SLAP2 overexpression or depletion in hematopoietic cell lines affects the down regulation of several RTKs, including CSF-1R, c-Kit and FLT3 [42][43][44]45 . Outside the hematopoietic system, SLAP is important for down regulation of SRC and EPHA2 signaling in intestinal epithelial cells as well as PDGFR signaling induced dorsal ruffle formation 46-48 . SLAP and SLAP2 are membrane associated proteins by virtue of an amino-terminal myristoylation site.…”

“…SLAP/SLAP2 recruitment to activated receptor TKs is mediated through the SH3/SH2 module, while the C-terminal tail region of both SLAP and SLAP2 constitutively associates with CBL 32,35,53 . SLAP association with CBL is important for ubiquitin dependent down regulation of ZAP-70 and TCRζ, as well as RTKs FLT3 and c-KIT 31,33,35,40,[43][44][45]54 .…”