Oncoprotein Networks

nucleophosmin (Npm) sequences, which are fused to the entire cytoplasmic domain of Alk, a receptor-like The increasing complexity of growth control pathways PTK (Morris et al., 1994; Fujimoto et al., 1996). The Telhas beenparalleled by the increasingly diverse functions PDGFb receptor fusion, generated by the t(5;12) translouncovered for oncoproteins and tumor suppressor procation in chronic myelomonocytic leukemia, joins the teins. Our awareness of the interconnections between N-terminal part of Tel, an Ets family transcription factor, growth factorand growth inhibitor-initiated signaling with the entire cytoplasmic domain of the PDGFbR PTK pathways has furthered our understanding of mechagene, resulting in dimerization through a helix-loop-helix nisms underlying malignant transformation, but at the motif in the Tel domain and constitutive PTK activation same time has indicated how complex cell growth con(Golub et al., 1994). trol networks will be. In the past few years, there has Tel proves to be a common fusion partner in leukemiabeen enormous progress in elucidating the details of associated chromosomal translocations. In acute mymitogenic signaling. The positioning of multiple oncoeloid leukemias carrying the t(12;9) translocation, most proteins and tumor suppressor proteins on the same of Tel, including the helix-loop-helix motif, is fused to pathway has underscored the importance of some of the Abl nonreceptor PTK upstream of the SH3 domain, these signaling pathways in transformation. For inresulting in a dimeric protein that is constitutively tyrostance, ErbB, Ras, and Raf all lie on the ERK MAP kinase sine phosphorylated, and localizes to the cytoskeleton (MAPK) pathway, which through phosphorylation of (Golub et al., 1996). This activation mechanism is similar members of the Ets protein family leads to induction of to that for Bcr-Abl, the product of the t(9;21) chromoimmediate early genes like c-fos. some fusion found in chronic myelogenous leukemia, The functions of oncoproteins and tumor suppressor where the N-terminal Bcr domain provides a coiled–coil proteins have been more than adequately reviewed in type oligomerization domain. However, oncogenic actiseveral places in the past few years. Taking this into vation of othernonreceptor PTKsdoes not involve fusion account, and given the space constraints, I have chosen with dimerization partners but rather loss of a negative to discuss examples of more recently discovered oncoregulatory function, as is the case for v-Src, where the proteins and tumor suppressor proteins that illustrate C-terminal regulatory tyrosine of c-Src is deleted. new principles of cell regulation, emphasizing how such Another receptor PTK, Ret, had been found to be oncogenically activated in multiple ways. Ret was origiprinciples allow us to establish a regulatory network.