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(Received for publication, July 1, 1996, and in revised form, August 15, 1996)
From the Laboratory of Cellular Development and Oncology, NIDR,
National Institutes of Health, Bethesda, Maryland 20892-4330
Certain small GTP-binding proteins control the
enzymatic activity of a family of closely related serine-threonine
kinases known as mitogen-activated protein kinases (MAPKs). In turn,
these MAPKs, such as p44mapk and p42mapk, referred to
herein as MAPKs, and stress-activated protein kinases, also termed
c-Jun N-terminal kinases (JNKs), phosphorylate and regulate the
activity of key molecules that ultimately control the expression of
genes essential for many cellular processes. Whereas Ras controls the
activation of MAPK, we and others have recently observed that two
members of the Rho family of small GTP-binding proteins, Rac1 and
Cdc42, regulate the activity of JNKs. The identity of molecules
communicating Rac1 and Cdc42 to JNK is still poorly understood. It has
been suggested that Pak1 is the most upstream kinase connecting these
GTPases to JNK; however, we have observed that coexpression of Pak1
with activated forms of Cdc42 or Rac1 diminishes rather than enhances
JNK activation. This prompted us to explore the possibility that
kinases other than Pak might participate in signaling from GTP-binding
proteins to JNK. In this regard, a computer-assisted search for
proteins containing areas of homology to that in Pak1 that is involved
in binding to Rac1 and Cdc42 led to the identification of mixed lineage
kinase 3 (MLK3), also known as protein-tyrosine kinase 1, as a
potential candidate for this function. In this study, we found that
MLK3 overexpression is sufficient to activate JNK potently
without affecting the phosphorylating activity of MAPK or p38.
Furthermore, we present evidence that MLK3 binds the GTP-binding
proteins Cdc42 and Rac1 in vivo and that MLK3
mediates activation of MEKK-SEK-JNK kinase cascade by Rac1 and Cdc42.
Taken together, these findings strongly suggest that members of the
novel MLK family of highly related kinases link small GTP-binding
proteins to the JNK signaling pathway.
Volume 271, Number 44,
Issue of November 1, 1996
pp. 27225-27228
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
A ROLE FOR MIXED LINEAGE KINASE 3/PROTEIN-TYROSINE KINASE 1, A
NOVEL MEMBER OF THE MIXED LINEAGE KINASE FAMILY
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