Recent work with interleukins has shown a convergence of tyrosine phosphorylation signal transduction cascades at the level of the Janus and Src families of tyrosine kinases. Here we demonstrate that activation of the seven-transmembrane AT 1 receptor by angiotensin II induces a physical association between Jak2 and Fyn, in vivo. This association requires the catalytic activity of Jak2 but not Fyn. Deletion studies indicate that the region of Jak2 that binds Fyn is located between amino acids 1 and 240. Studies of the Fyn SH2 and SH3 domains demonstrate that the SH2 domain plays the primary role in Jak2/Fyn association. Not surprisingly, this domain shows a marked preference for tyrosinephosphorylated Jak2. Surface plasmon resonance estimated the dissociation equilibrium constant (K d ) of this association to be 2.36 nM. Last, in vivo studies in vascular smooth muscle cells show that, in response to angiotensin II, Jak2 activation is required for Fyn activation and induction of the c-fos gene. The significance of these data is that Jak2, in addition to serving as a critical angiotensin II activated signal transduction kinase, also functions as a docking protein and participates in the activation of Fyn by providing phosphotyrosine residues that bind the SH2 domain of Fyn.The Jak family of nonreceptor tyrosine kinases includes Jak1, Jak2, Jak3, and Tyk2. Each protein is approximately 130 kDa and contains seven conserved Jak homology domains (JH1 to JH7) (1, 2). The Jak kinases induce gene regulation through the signal transducers and activators of transcription. Unlike almost all other protein-tyrosine kinases, members of the Jak family bear no SH2 1 or SH3 domains. In contrast to the Jaks, members of the Src family of protein-tyrosine kinases are approximately 55-62 kDa in mass and do possess SH2 and SH3 domains. There are nine known members of the Src kinase family. While the expression of most members is restricted to hematopoietic cells, Fyn and Src are widely expressed by many cell types. There appears to be some functional redundancy of these two proteins, since knockout mice lacking either gene are born alive, while disruption of both the fyn and src alleles results in embryonic lethality (3-5). This redundancy is also seen in the activation of similar signaling pathways by Fyn and Src (6).Recent studies have demonstrated various levels of crosstalk between Jak2 and other signaling pathways. For example, activation of gp130 by the hematopoietic cytokine, interleukin-11, induces protein complex formation between the Jak and Src family tyrosine kinases. Specifically, treatment of 3T3-L1 cells with interleukin-11 leads to a transient complex of Grb2, Jak2, and Fyn (7). Subsequent studies by Yang et al. demonstrated an interleukin-11-dependent association of Jak2 with other signaling molecules including protein phosphatase 2A, phosphatidylinositol-3-kinase, and the Src family kinase Yes (8). To date, the regions that mediate these interactions, as well as the hierarchy of the signal transduction cascades, hav...

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