Joseph Kissil, Ph.D.

Assistant Professor
Molecular and Cellular Oncogenesis Program
215-898-3874, Office
215-898-3792, Fax

Introduction

Our lab is studying signaling networks that relay information from the extra-cellular environment into cells. These signaling pathways are involved in almost every aspect of inter- and intracellular communication and their deregulation often leads to pathological conditions, such as cancer. We are interested in understanding how various pathways communicate with one another, under normal conditions, and how the deregulation of this crosstalk manifests as disease.

Research Summary

Research over the past several years has significantly enhanced our knowledge of signal transduction pathways. Major efforts are underway to integrate this data into a comprehensive map of cellular signaling networks. The Ras and Rac families of protein are small GTP-binding proteins, which function as molecular switches. The Ras-proteins were originally identified as oncogenes and their role in transformation and cancer is well established. They regulate an extensive number of cellular processes through a few signaling pathways, including the PI3-kinase, MAP-kinase, Ral-GDS and Rac pathways. The Rac proteins are members of the Rho family of small G-proteins, and are also implicated in the regulation of several pathways, including those leading to cytoskeleton reorganization, gene expression, and endocytosis. Recent work from our lab has demonstrated that Rac signaling is required for Ras-signal transduction and transformation.

We have recently found an additional link between the Rac-signaling pathways and cancer in the case of Neurofibromatosis type 2 (NF2), an inherited disorder that is characterized mainly by development of Schwann cell tumors of the eighth cranial nerve. The NF2 gene is a tumor suppressor gene coding for a protein called merlin, which is highly homologous to the ERM proteins moesin, ezrin, and radixin. Merlin is regulated by phosphorylation induced by Rac/cdc42 via the p21-activated kinases (Pak1 and 2) and functions as a negative regulator of Rac signaling through its direct inhibitory function on Pak1. We are currently assessing whether this function is indeed the tumor suppressive function of merlin. In addition, we are working on establishing whether targeting the p21-activated kinases would be beneficial as a treatment modality for neurofibromatosis type 2.

Selected Publications

Yi C, Wilker EW, Yaffe MB, Stemmer-Rachamimov A, Kissil JL. Validation of the p-21-activated kinases as targets for inhibition in neurofibromatosis type 2. Cancer Research. 2008 Oct. 1; 68(19):7932-7.

Kissil JL. Walmsley MJ. Hanlon L. Haigis KM. Bender Kim CF. ... Capobianco AJ. Tybulewicz VL. Jacks T. Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Research. 2007 Sep. 1; 67(17):8089-94.

Yi, C., McCarty, JH., Troutman, SA., Eckman, MS., Bronson, RT., and Kissil, JL. “Loss of the putative tumor suppressor band 4.1B/Dal1 gene is dispensable for normal development and does not predispose to cancer.” (2005) Molecular and Cellular Biology. 25(22):10052-9.