LYN AND JAK2 IN GCSF PROLIFERATIVE SIGNALING

Children'S Hosp Pittsburgh/Upmc Hlth Sys, Pittsburgh PA

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Abstract

DESCRIPTION: (Adapted from investigator's abstract) Over the past several years, a great deal of attention has centered on the Jak family of protein tyrosine kinases (PTK). A wide range of cytokines lead to the tyrosine phosphorylation of one of the Jak-related PTK, and current dogma holds that the Jaks are the principal signaling PTK for cytokine receptors. However, the investigators have identified Lyn as a rapidly activated signaling molecule for FM-CSF and G-CSF, two important growth factors for white blood cell development. Lyn is a Src kinase which has been best studied in the context of B cell receptor signaling. Nonetheless, it is one of the least understood members of the Src family. More recent studies in their laboratory with wild-type B cells and the mutagenized lyn-deficient cell lines, which have been stably transfected with the human G-CSF receptor, have shown that G-CSF's induction of DNA synthesis requires Lyn and that the activation of Jak1 or Jak2 is not sufficient for that response. Ectopic expression of Lyn, but not that of c-Src, restored mitogenic responsiveness to G-CSF in the lyn-deficient cells. While wild type cells which expressed kinase-inactive Jak2 still responded to G-CSF with induction of DNA synthesis, the cells which expressed kinase-inactive Lyn did not. The investigator's hypothesis is that Lyn and Jak are two proximal PTK pathways for G-csf signaling. The specific aims of this proposal are to: 1) determine the structural mechanisms whereby Lyn and Jak2 interact with the G-CSFR; 2) define the relative contributions of Lyn and Jak2 in hematopoietic cell signaling by transfecting; and 3) identify Lyn-specific and Jak2-specific signaling partners through the yeast two-hybrid screen.