Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2

Insulin receptor substrates (IRSs) are adaptor proteins that link signaling from upstream activators to multiple downstream effectors to modulate normal growth, metabolism, survival, and differentiation. Recent cell culture studies have shown that IRSs can interact with, and are functionally required for, the transforming ability of many oncogenes. Consistent with this, IRSs are elevated and hyperactive in many human tumors. IRSs respond to many extracellular signals that are critical for mammary gland development, and we have shown that IRSs disrupt normal mammary acini formation in vitro, and cause mammary tumorigenesis and metastasis in vivo. In this review we will discuss the role of IRSs in both transformation and cancer progression.