STE20-homologous proteins have been implicated in mammalian MAP kinase pathways as important transducers of signals from p21 family GTPases. We have cloned a novel STE20 family member, which we call KHS for kinase homologous to SPS1/STE20, that encodes a kinase of 95 kD which is expressed in a variety of tissues. Transiently expressed fusion protein GST-KHS exhibits phosphotransferase activity toward a panel of test substrates, including myelin basic protein (MBP), which is phosphorylated by all known STE20 homologues. KHS is most closely related to another human STE20, GC kinase (74% similar in the catalytic domain), which has recently been placed upstream of the stress-activated MAP kinases (SAPKs/JNKs. KHS also activates JNK in transient coexpression experiments, suggesting a role for KHS in the stress response of ®broblasts. Characterization and comparison of the regulation of these two kinases will be important in elucidating MAP kinase signalling cascades.
The binding of growth factors to their cognate receptors at the plasma membrane elicits a variety of biochemical and genomic changes that lead ultimately to cell proliferation or to differentiation. One of the cellular responses is the transcriptional activation of immediate-early genes. While much attention has focused on the identification and characterization of these genes, the mechanisms linking receptor occupancy to their rapid and transient expression remain largely unknown. The identification of some of these transcription factors as phosphoproteins has implied the involvement of protein phosphorylation in transcriptional regulation [ 11. However, the nature of the growth-responsive kinases that participate in this process has not yet been elucidated.Several protein serinelthreonine kinases that participate in regulating cell growth and development have been identified recently. Among these are two distinct families of 40 S ribosomal protein S6 kinases, pp9OrSk (RSK, 90 kDa-ribosomal S6 kinase) and pp7OShk (70 kDa-ribosomal S6 kinase) [2, 31. These protein serine/threonine kinases are differentially regulated by a variety of mitogens via distinct signalling cascades [4, 51. Both enzymes are regulated by serinelthreonine phosphorylation, suggesting that protein serinelthreonine kinases exist upstream in the signalling pathways that regulate these enzymes. While the putative ~~7 0 "~~ protein kinase has not yet been identified, several studies have provided evidence that pp9OrSk is phosphorylated and activated by mitogen-activated protein kinases (MAP kinases) [6, 71. MAP k' inases have been shown to be activated by phosphorylation both at threonine and at tyrosine residues in many types of cells in response to various extracellular stimuli [8].In this paper, we demonstrate that MAP kinases and RSK are localized in the nucleus as well as in the cytoplasm of cultured cells. The activated enzymes can phosphorylate several nuclear Abbreviations used: MAP kinase, mitogen-activated protein kinase; RSK, 90 kDa ribosomal S6 kinase; SKE, serum response element; SRF, serum response factor. ?To whom correspondence should be addressed. $Present address: Robert Wood Johnson Medical School, CAHM, Piscataway, NJ 08854, U.S.A.proteins in vitro efficiently, including transcription factors that are the products of, or are involved in the regulation of, immediate-early genes. Detailed characterization of the phosphorylation of one of the substrates, C-FOS, reveals that MAP kinase and RSK co-ordinately phosphorylate c-Fos in the C-terminal trans-repression domain. This study presents a protein kinase cascade that is capable of transducing signals from the cytoplasm to the nucleus with the potential to modulate growthresponsive gene expression both positively and negatively. MAP kinase and RSK are localized in the cytoplasm and in the nucleusMAP kinases and RSK were originally isolated as cytosolic enzymes. However, their subcellular distribution has not been characterized in detail. Antisera made against the predicted C-termi...
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