[Frontiers in Bioscience 7, d376-389, February 1, 2002]

ROLES OF ERBB FAMILY RECEPTOR TYROSINE KINASES, AND DOWNSTREAM SIGNALING PATHWAYS, IN THE CONTROL OF CELL GROWTH AND SURVIVAL

Steven Grant 2, 3 Liang Qiao 1, and Paul Dent 1,3

Departments of 1 Radiation Oncology, 2 Hematology/Oncology, and 3 Pharmacology and Toxicology, Medical College of Virginia,Virginia Commonwealth University, Richmond VA 23298-0058

TABLE OF CONTENTS

1. Abstract
2. The ErbB family of receptor tyrosine kinases
3. The mitogen activated protein kinase (MAPK) and
4. Inhibitors of ErbB receptors can modify the growth and survival of normal and tumor cells phosphatidyl inositol 3-kinase (PI3K) pathways
5. Pathways downstream of ErbB family receptors can mediate survival signaling
6. The regulation of two putative caspase cascades (in a simplified manner)
7. Conclusions
8. References

1. ABSTRACT

Within the last 20 years, multiple novel intracellular signal transduction pathways, downstream of plasma membrane receptors, have been discovered. These pathways have been linked to the regulation of diverse cellular events such as proliferation, senescence, differentiation and apoptosis. This review will focus upon the roles of signaling by the ErbB receptor tyrosine kinase family (ErbB1-4) in the survival of cells in response to cytotoxic stresses. In addition, plasma membrane-to-nucleus signaling pathways downstream of these receptors, such as mitogen activated protein kinase (MAPK) and phosphatidyl inositol 3-kinase (PI3K), in the control of cell survival will be discussed. Recent evidence suggests that signaling by the MAPK and PI3K pathways can both enhance proliferation as well as protect cells from apoptosis. We describe potential mechanisms by which modulation of pathway activities following inhibition of ErbB receptor function may alter the sensitivity of cells to toxic insults, leading to increased apoptosis and loss of clonogenic survival.