Axel H. Schönthal

Department of Molecular Microbiology and Immunology, K. Norris Jr. Comprehensive Cancer Center, University of Southern California, 2011 Zonal Ave., HMR-405, Los Angeles, CA 90033

Received 8/25/98 Accepted 12/2/98

2. INTRODUCTION

Control of cellular growth and differentiation is a prerequisite for the proper development of higher eukaryotic organisms. Extracellular molecules, such as hormones or growth factors, are important agents in determining this control. The genetic response of cells to these molecules often requires signal receptors, signal transduction (second and third messengers), and usually alterations in the activity of transcription factors which activate or repress target genes. The importance of adequate regulation of these signal transduction pathways has been emphasized by the finding that many protein products of protooncogenes are components of this network. If mutated or inappropriately expressed, they become oncoproteins that are able to cause unrestricted cellular growth and carcinogenesis (1).

A hallmark of these growth-regulatory signal transduction pathways is the reversible phosphorylation of proteins. Many growth factor receptors are kinases; upon binding of their respective ligand, their enzymatic activity becomes activated and initiates kinase cascades that transmit the signal to the nucleus. There, the gene-proximal targets, transcription factors, are being phosphorylated and cause changes in the activity of gene expression. As a consequence, the altered pattern of gene expression will generate the respective phenotypic response, such as, for example, cell proliferation, differentiation, or apoptosis (2, 3).

Many of the (proto)oncogene products are kinases, and it has been demonstrated that this enzymatic activity is an absolute requirement for their normal function, as well as for the process of tumorigenic transformation by these proteins. Similarly, several tumor suppressor gene products are strictly regulated by reversible phosphorylation reactions as well. For example, the retinoblastoma (RB) protein is active (growth suppressive) when it is unphosphorylated, but becomes inactivated by hyperphosphorylation (4, 5).

While the role of protein kinases in the above mentioned processes has been well established, the contribution of protein phosphatases is less clear and has only recently received more investigative attention. However, the finding that some phosphatases are crucial components of pathways that regulate cellular growth and therefore may play a role in the process of tumorigenic transformation, has brought them to the forefront of cancer research (6). So far, only very few phosphatases have been directly implicated in the etiology of tumors: the dual-specificity protein phosphatases CDC25A and CDC25B, which are able to transform cells in culture (7), and thus can be classified as oncogenes; the dual-specificity protein phosphatase PTEN (MMAC1) which is frequently found mutated or deleted in advanced cancers and behaves like a tumor suppressor gene (8). A further important regulator of signal transduction and cell growth is the serine/threonine protein phosphatase type 2A (PP2A) which will be discussed in detail below.