RasGRP Ras guanine nucleotide exchange factors in cancer

Abstract

RasGRP proteins are activators of Ras and other related small GTPases by the virtue of functioning as guanine nucleotide exchange factors (GEFs). In vertebrates, four RasGRP family members have been described. RasGRP-1 through-4 share many structural domains but there are also subtle differences between each of the different family members. Whereas SOS RasGEFs are ubiquitously expressed, RasGRP proteins are expressed in distinct patterns, such as in different cells of the hematopoietic system and in the brain. Most studies have concentrated on the role of RasGRP proteins in the development and function of immune cell types because of the predominant RasGRP expression profiles in these cells and the immune phenotypes of mice deficient for Rasgrp genes. However, more recent studies demonstrate that RasGRPs also play an important role in tumorigenesis. Examples are skin- and hematological-cancers but also solid malignancies such as melanoma or prostate cancer. These novel studies bring up many new and unanswered questions related to the molecular mechanism of RasGRP-driven oncogenesis, such as new receptor systems that RasGRP appears to respond to as well as regulatory mechanisms for RasGRP expression that appear to be perturbed in these cancers. Here we will review some of the known aspects of RasGRP biology in lymphocytes and will discuss the exciting new notion that RasGRP Ras exchange factors play a role in oncogenesis downstream of various growth factor receptors.

Keywords

Ras / signaling / lymphocytes / cancer / RasGRP / receptor

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Acknowledgments

We thank Anna Hupalowska for generating all the illustrations for this review and all the members of the Roose laboratory for useful insights. Olga Ksionda, Andre Limnander, Jeroen Roose, and the research in the Roose laboratory is supported by a Sandler Program in Basic Science (start-up JPR), NIH-NCI Physical Science Oncology Center grant U54CA143874 (JPR), NIH grant 1P01AI091580-01 (JPR), a Gabrielle’s Angel Foundation grants (JPR), a UCSF PBBR/Sanofi Leap to Innovation for Therapeutics and Technology (LIFTT) Program ant (JPR), and a NIH grant 1R03AR062783-01A1 (Al).

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