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.
Highlights
The SRC Kinase Adaptor Phosphoprotein 2 (SKAP2), a broadly expressed protein conserved among gnathostomes and recruiting protein partners to specific subcellular domains, plays a central role in multiple physiological processes, including response to TGFβ [1], integrin signaling [2], control of actin-polymerization [3, 4], podosome stabilization, metastatic progression [5], and cell migration [6]
SRC kinases were selected as putative interactors because some of them have been described as SKAP2 interactors [9, 10, 16]
We developed a luciferase complementation assay to analyze interaction between SKAP2 and 17 putative protein partners
Summary
The SRC Kinase Adaptor Phosphoprotein 2 (SKAP2), a broadly expressed protein conserved among gnathostomes and recruiting protein partners to specific subcellular domains, plays a central role in multiple physiological processes, including response to TGFβ [1], integrin signaling [2], control of actin-polymerization [3, 4], podosome stabilization, metastatic progression [5], and cell migration [6]. Skap interacts with the Riam-Fyb complex as Skap, a paralog playing a non-redundant www.impactjournals.com/oncotarget functional role [15]. This complex stabilizes the TCR at the immune synapses. High expression of SKAP2 is associated with poor prognosis in non-small cell lung cancer [18]. This protein is highly expressed in the CNS under the control of retinoic acid and during development [9]. In the lens of the eye, SKAP2 is a novel target of HSF4b, which associates with NCK2 adaptor but not with its NCK1 homolog [19]
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