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Review
. 2015 Oct 20;42(10):521-529.
doi: 10.1016/j.jgg.2015.09.001. Epub 2015 Sep 12.

Oncogenic Signaling Adaptor Proteins

Leo Y Luo  1 , William C Hahn  2
Affiliations
Review

Oncogenic Signaling Adaptor Proteins

Leo Y Luo et al. J Genet Genomics. .

Abstract

Signal transduction pathways activated by receptor tyrosine kinases (RTK) play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we focus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes, CRKL, GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.

Keywords: Adaptor protein; Cancer; Oncogene.

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Figures

Fig. 1
Fig. 1
Schematic representation of CRKL, GAB2, and FRS2. The CRKL protein structure contains one SH2 (Src homology 2) domain that binds to p130CAS (also known as BCAR1), paxillin, and GAB1, and two SH3 (Src homology 3) domains (SH3N and SH3C) that interact with RAPGEF1, DOCK1, and SOS. Structural domains of GAB2 include an N-terminal PH (Pleckstrin homology) domain critical for membrane localization, central proline-rich (Pro-H) domains that interact with SH2 and SH3 domain-containing proteins such as GRB2, and multiple phosphorylation sites are also present to bind to signaling partners such as PLC-γ, CRK, SHP2, and p85. FRS2α contains an N-terminal myristoylation site for membrane anchoring, a C-terminal phosphotyrosine binding (PTB) domain that interacts with limited species of receptors. It also includes multiple tyrosine phosphorylation sites that bind to SH2 domains of GRB2 and GAB1.
Fig. 2
Fig. 2
Overview of the signaling pathways associated with CRKL, GAB2, and FRS2. CRKL is activated by multiple types of cell surface receptors including integrin receptors upon binding to extracellular matrix (ECM), cytokine receptors, and growth factor receptors. GAB2 and FRS2 are primarily activated by growth factor receptors. FRS2 exhibits more specificity towards fibroblast growth factor receptors and neutrophin receptors. All three adaptor proteins lead to Ras/MAPK and PI3K/AKT pathway activation that promote cancer initiation and progression.
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