Stem cell factor (SCF) is a growth factor which promotes viability as well as elicits proliferation and differentiation in hematopoietic progenitor and stem cells. In addition to its effects as a single factor, SCF acts synergistically with other growth factors to stimulate dramatic increases in proliferation of hematopoietic cells. The research objective of this project is to delineate the biochemical mechanisms through which SCF acts as a single factor as well as in combination with other hematopoietic growth factors. The receptor for SCF is the receptor tyrosine kinase c-kit. Receptor tyrosine kinases increase gene transcription through three biochemical pathways, the ras-raf-MAP kinase cascade, the JAK/STAT pathway and induction of c-myc through Src family members. Interestingly, little is known about the role of the JAK/STAT pathway and the Src family pathway in SCF-mediated responses. We have examined the role of the Src family and the JAK family of protein tyrosine kinases in SCF signal transduction. Our studies have demonstrated that the SCF receptor is constitutively complexed with both JAK2 and Lyn. Treatment of cells with SCF results in a rapid and transient phosphorylation of JAK2 while activation of Lyn is somewhat slower and more protracted. In studies using antisense oligonucleotides, Lyn was found to be critical for SCF-induced proliferation while activation of JAK2 was necessary to achieve optimal proliferative responses. One of the downstream effectors well characterized in the signal transduction pathway of Janus family members are signal transducers and activators of transcription (STATs). We have examined the effect of SCF on Stat 1, a STAT family member known to be activated by several receptor tyrosine kinase ligands. SCF induced association of Stat 1 and c- kit, tyrosine phosphorylation of Stat 1 and DNA binding activity of Stat 1. Presently, this project is focused on 1) defining the regions of c-kit which mediate activation of Lyn, JAK2 and Stat 1; and 2) determining the role of each of these signal transduction components in SCF-mediated survival, proliferation and differentiation.
| Shivakrupa, R; Linnekin, Diana (2005) Lyn contributes to regulation of multiple Kit-dependent signaling pathways in murine bone marrow mast cells. Cell Signal 17:103-9 |
| Lennartsson, Johan; Shivakrupa, R; Linnekin, Diana (2004) Synergistic growth of stem cell factor and granulocyte macrophage colony-stimulating factor involves kinase-dependent and -independent contributions from c-Kit. J Biol Chem 279:44544-53 |
| Shivakrupa, R; Bernstein, Alan; Watring, Nicole et al. (2003) Phosphatidylinositol 3'-kinase is required for growth of mast cells expressing the kit catalytic domain mutant. Cancer Res 63:4412-9 |
