Oncogenic Signaling Adaptor Proteins

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.

Age-related gene expression changes, and transcriptome wide association study of physical and cognitive aging traits, in the Lothian Birth Cohort 1936

“…ER stress influences number of diseases including neurodegeneration and cardiovascular disease [ 43 ]. GAB2 encodes a member of the GRB2-associated binding protein (GAB) gene family and is associated with human tumorigenesis, particularly in breast cancer, leukemia and melanoma [ 44 ]. FAM167A is located in a locus previously associated with autoimmune diseases [ 45 ].…”

Myristoylation-Dependent Palmitoylation of the Receptor Tyrosine Kinase Adaptor FRS2α

“…Because FGF signaling regulates cell differentiation, growth, survival, and motility, it is not surprising that FRS2α is being actively pursued as a possible therapeutic target in cancer. 24,25 Myristoylation of FRS2α was recently proposed as a promising cancer drug target, offering the possibility of circumventing the resistance observed with the use of FGFR kinase inhibitors. 6 Our results suggest that protein acyltransferases and thioesterases that regulate FRS2 palmitoylation should also be considered as potential targets for therapeutic intervention in cancer and other growth factor-related diseases.…”

Emerging Roles of Downstream of Kinase 3 in Cell Signaling

“…High affinity regions termed “hot spots” which drive protein binding have been mapped onto protein-protein interfaces, and these hot spots are particularly adept at binding small-molecule or peptide inhibitors ( 32 , 33 ). Such inhibitors of adaptors will have the advantage of higher efficacy and increased specificity, and as such reduced toxicity, as compared to conventional kinase inhibitors, which are often non-specific due to the highly conserved nature of the kinase domains ( 34 ). Hence, it will be feasible to design and develop inhibitors which disrupt Dok-3 binding with their interacting partners for therapeutic interventions.…”