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J Biol Chem, Vol. 274, Issue 47, 33287-33295, November 19, 1999
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From the Mammalian members related to Saccharomyces
cerevisiae serine/threonine kinase STE20 can be divided into two
subfamilies based on their structure and function. The PAK subfamily is
characterized by an N-terminal p21-binding domain (also known as CRIB
domain), a C-terminal kinase domain, and is regulated by the small
GTP-binding proteins Rac1 and Cdc42Hs. The second group is represented
by the GCK-like members, which contain an N-terminal catalytic domain and lack the p21-binding domain. Some of them have been demonstrated to
induce c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) cascade, while others have been shown to be activated by a
subset of stress conditions or apoptotic agents, although little is
known about their specific function. Here, we have identified a novel
human STE20-related serine/threonine kinase, belonging to the GCK-like
subfamily. This kinase does not induce the JNK/SAPK pathway, but,
instead, inhibits the basal activity of JNK/SAPK, and diminishes its
activation in response to human epidermal growth factor (EGF).
Therefore, we designated this molecule JIK for
JNK/SAPK-inhibitory kinase. The
inhibition of JNK/SAPK signaling pathway by JIK was found to occur
between the EGF receptor and the small GTP-binding proteins Rac1 and
Cdc42Hs. In contrast, JIK does not activate nor does it inhibit ERK2,
ERK6, p38, or ERK5. Furthermore, JIK kinase activity is not modulated
by any exogenous stimuli, but, interestingly, it is dramatically
decreased upon EGF receptor activation. Thus, JIK might represent the
first member of the STE20 kinase family whose activity can be
negatively regulated by tyrosine kinase receptors, and whose downstream
targets inhibit, rather than enhance, JNK/SAPK activation.
Oral and Pharyngeal Cancer Branch, NIDCR,
National Institutes of Health, Bethesda, Maryland 20892-4330, the
§ Institute of Virology, Slovak Academy of Sciences,
Dubravska Cesta 9, Bratislava 84246, Slovak Republic, the
¶ Department of Experimental Oncology, European Institute of
Oncology, Milan 20140, Italy, and ** GenoQuest, Inc.,
Germantown, Maryland 20874
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