TYROSINE KINASE RECEPTOR-ACTIVATED SIGNAL-TRANSDUCTION PATHWAYS WHICHLEAD TO ONCOGENESIS

Oncogenesis is a complicated process involving signal transduction pat hways that mediate many different physiological events. Typically, onc ogenes cause unregulated cell growth and this phenotype has been attri buted to the growth-stimulating activity of oncogenes such as I as and src. In recent years, much research effort has focused an proteins th at function downstream of Ras, leading to the identification of the Ra s/Raf/MAPK pathway, because activation of this pathway leads to cellul ar proliferation. Activated receptor tyrosine kinases (RTKs) also util ize this pathway to mediate their growth-stimulating effects. However, RTKs activate many other signaling proteins that are not involved in the cellular proliferation process, pel se and me are learning that th ese pathways also contribute to the oncogenic process. In fact, RTKs a nd many of the proteins involved in RTK-dependent signal transduction can also function as oncogenes, For example, the catalytic subunit of phosphoinositide 3-kinase (PI3-K) was recently identified as an oncoge nic protein. The scope of pathways that are activated by oncogenic RTK s is expanding. Thus, not only do RTKs activate Ras-dependent pathways that drive proliferation, RTKs activate PI3-K-dependent pathways whic h also contribute to the oncogenic mechanism. PI3-K can initiate chang es in gene transcription, cytoskeletal changes through beta-catenin, c hanges in cell motility through the tumor suppressor, adenomatous poly posis coli (APC), and phosphorylation of BAD, a protein involved in ap optotic and anti-apoptotic signaling. There is also cross-talk between RTKs and the oncostatin cytokine receptor which may positively and ne gatively influence oncogenesis, For this review, we will focus on onco genic RTKs and the network of cellular proteins that are activated by RTKs because multiple, divergent pathways are responsible for oncogene sis.