Molecular analysis of the granulocyte colony-stimulating factor receptor

Abstract

G-CSF is the major growth factor responsible for regulating granulopoiesis and promotes the survival, proliferation, functional activation, and maturation of cells of the neutrophil lineage. These biologic activities are mediated by distinct cytoplasmic regions of the G-CSFR. The membrane-proximal region is required for mitogenic signaling, whereas the distal carboxy-terminal portion mediates myeloid maturation signals and inhibits growth signaling. An intervening region of 30 amino acids strongly enhances the G-CSF-triggered growth stimulus. The existence of multiple G-CSFR classes which differ in their cytoplasmic sequences and exhibit differing signaling properties suggests that they may function to tightly regulate myeloid cell proliferation and maturation in response to G-CSF. A rudimentary framework for signaling by the G-CSFR has evolved involving activation of the Jak-Stat and Ras-MAP kinase pathways. Although the precise roles of these pathways in signaling by the G-CSFR have not been fully elucidated, activation of Jak kinases, but not Stat transcription factors, and MAP kinase tyrosine phosphorylation appear to correlate with mitogenic responses. In nonproliferating terminally differentiated cells, G- CSF activates different signaling pathways that do not appear to involve any of the known Jak or Stat kinases or the Ras-MAP kinase pathway. The physiologic relevance of Lyn/Syk activation to G-CSFR signaling in neutrophils and induction of myeloid maturation signals awaits further studies. Targeted disruption of Jak/Stat genes should also make it possible to better define the roles of these kinases in G-CSFR signaling. Recently, point mutations in the G-CSFR gene resulting in disruption of myeloid maturation have been reported in some patients with SCN. Somatic mutations resulting in truncations of the carboxy- terminal region of the G-CSFR have also been reported in some patients with AML and represent a novel mechanism for leukemogenesis. These truncations disrupt the maturation signaling function of the normal wild-type G-CSFR (class I) and lead to hyperproliferative responses to G-CSF through a dominant-negative mechanism. The identification of distinct functional subdomains in the cytoplasmic region of the G-CSFR that mediate myeloid proliferation and maturation responses and characterization of the signaling molecules with which these subdomains interact has important implications for understanding the pathological mechanisms involved in disorders of granulopoiesis. Further clarification of the contribution of mutations in the G-CSFR gene to the evolution of AML will require a detailed understanding of the G-CSFR. Information pertaining to the signaling pathways activated by the G-CSFR will likely prove to be important in the development of novel drugs that actively induce or inhibit myeloid cell proliferation or maturation depending upon the desired response.