The long term objectives of this research proposal are to characterize the signaling pathways downstream of the tyrosine kinase Jak2 which are critical for hematopoietic cell development. That Jak2 plays a critical role in hematopoiesis is demonstrated by the complete absence of several myeloid lineages in mice lacking a functional JAK2 gene. Furthermore, its importance in hematological development is underscored by the recent discovery that leukemic cells of several patients with different hematological malignancies contain an abnormal fusion protein comprised of the transcription factor TEL fused to the catalytic domain of JAK2. Although the signaling cascades activated by Jak2 are not well characterized, recent data suggests that tyrosine autophosphorylation of Jak2 is functionally important. One critical goal of this proposal is to analyze the autophosphorylation sites of JAK2. This will be accomplished, in part, by reconstituting Jak2-/- fetal liver cells with either wild-type or tyrosine-to-phenylalanine point mutants of Jak2, and functionally analyzing the cells by in vitro colony formation or in vivo reconstitution ability. Another important goal will be to identify and characterize molecules which interact directly with phosphorylated Jak2. Such molecules are good candidate Jak2 effector molecules. Thus, this study approaches the problem of studying Jak2 signaling on two fronts: firstly by analyzing Jak2 itself, and secondly, by analyzing the molecules which interact with Jak2.
| Carpino, Nick; Turner, Steve; Mekala, Divya et al. (2004) Regulation of ZAP-70 activation and TCR signaling by two related proteins, Sts-1 and Sts-2. Immunity 20:37-46 |
| Carpino, Nick; Thierfelder, William E; Chang, Ming-shi et al. (2004) Absence of an essential role for thymic stromal lymphopoietin receptor in murine B-cell development. Mol Cell Biol 24:2584-92 |
| Carpino, Nick; Kobayashi, Ryuji; Zang, Heesuk et al. (2002) Identification, cDNA cloning, and targeted deletion of p70, a novel, ubiquitously expressed SH3 domain-containing protein. Mol Cell Biol 22:7491-500 |
