A critical step in growth hormone (GH) signalling is the GH-induced activation of the GH receptor (GHR)-associated tyrosine kinase, JAK2. JAK2 is a 120 kD member of the Janus family of tyrosine kinases, whose other mammalian members include JAK1, JAK3, and TYK2. Using 3T3-F442A murine preadipocytes, we now report detection of a M(r) ~ 170 kD protein, referred to as HMW ('high molecular weight') JAK2, that is specifically reactive in immunoprecipitation and immunoblotting experiments with three independently-derived anti-JAK2 antibodies - two directed at carboxyl-terminal regions of the molecule and one directed at the amino-terminus. Like JAK2, HMW JAK2 is tyrosine phosphorylated in response to GH treatment of cells and is coimmunoprecipitated with anti-GHR serum. Thus, HMW JAK2 is a protein not heretofore described that is immunologically related to JAK2 and is physically and functionally associated with the GHR.