The SRC-family tyrosine kinase HCK shapes the landscape of SKAP2 interactome

Abstract

The SRC Kinase Adaptor Phosphoprotein 2 (SKAP2) is a broadly expressed adaptor associated with the control of actin-polymerization, cell migration, and oncogenesis. After activation of different receptors at the cell surface, this dimeric protein serves as a platform for assembling other adaptors such as FYB and some SRC family kinase members, although these mechanisms are still poorly understood. The goal of this study is to map the SKAP2 interactome and characterize which domains or binding motifs are involved in these interactions. This is a prerequisite to finely analyze how these pathways are integrated in the cell machinery and to study their role in cancer and other human diseases when this network of interactions is perturbed. In this work, the domain and the binding motif of fourteen proteins interacting with SKAP2 were precisely defined and a new interactor, FAM102A was discovered. Herein, a fine-tuning between the binding of SRC kinases and their activation was identified. This last process, which depends on SKAP2 dimerization, indirectly affects the binding of FYB protein. Analysis of conformational changes associated with activation/inhibition of SRC family members, presently limited to their effect on kinase activity, is extended to their interactive network, which paves the way for therapeutic development.

Identification of Novel Genes in Osteoarthritic Fibroblast-Like Synoviocytes Using Next-Generation Sequencing and Bioinformatics Approaches

“…SKAP2 encodes src kinase associated phosphoprotein 2 and participates in different physiological processes, including integrin signaling, cell migration and cancer progression 55. Alenghat et al .…”

SKAP2 as a new regulator of oligodendroglial migration and myelin sheath formation

“…SKAP2 is an adaptor protein with many binding sites and a variety of binding partners regulating its activity and conformational changes (Zhou et al , 2011; Alenghat et al , 2012; Ayoub et al , 2013; Tanaka et al , 2016; Bureau et al , 2018). This is in line with our observation that SKAP2 acts generally as a positive regulator of oligodendroglial migration, but negatively affects OPC migration after integrin activation by stimulation with pRGD.…”

“…SKAP2 ( src-kinase associated protein 2 ) is a cytoplasmic adapter protein that is expressed in several cell types such as lymphocytes, monocytes and neutrophils and which is required for global actin reorganization during cell migration (Alenghat et al , 2012; Boras et al , 2017). SKAP2 that has been first described in 1998 (Marie-Cardine et al , 1998), contains a pleckstrin homology (PH) domain, multiple tyrosine phosphorylation sites, C-terminal Src-Homology 3 domain (SH3 domain) and an N- terminal coiled-coil domain (Bureau et al , 2018). It interacts with different molecules implicated in integrin signaling events, including the adhesion and degranulation- promoting adaptor protein (ADAP) and RAP1-GTP–interacting adaptor molecule (RIAM) (Asazuma et al , 2000; Königsberger et al , 2010; Alenghat et al , 2012; Boras et al , 2017).…”

Interaction Network Provides Clues on the Role of BCAR1 in Cellular Response to Changes in Gravity

“…CBL is a further protein that interacts with BCAR1 via the SD-bound CRK [58] and had attracted attention in microgravity research. Associated with BCAR1 and CRK, CBL catalyzes the link of ubiquitin to several different target proteins, initiating their degradation [59][60][61]. Linking ubiquitin or ubiquitin-like molecules to the ε-amino group of lysine residues in target proteins regulates many cellular processes [112,113].…”

“…Being a member of CBL-BCAR1-CRK (or NCK) complexes, CBL exerts several regulatory functions by mediating the ubiquitination and degradation of various proteins in a negative feedback manner [59]. Amongst those proteins are members of the src-family kinases [60,61], including lyn-and fyn-kinases (see Table 1), which are known to phosphorylate the SD domain of BCAR1 [62,63]. Associated with the SH3 domain-containing kinase-binding protein 1 (SH3KBP1 or CIN85), CBL forms another complex with BCAR1 [64].…”