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PMID: 9891069 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase.

Molecular and cellular biology ·Vol. 19 ·No. 2 ·1999-02-00 ·Pages 1359-68

Ling P, Yao Z, Meyer CF, Wang XS, Oehrl W, Feller SM, Tan TH

Abstract

Hematopoietic progenitor kinase 1 (HPK1), a mammalian Ste20-related protein kinase, is an upstream activator of c-Jun N-terminal kinase (JNK). In order to further characterize the HPK1-mediated JNK signaling cascade, we searched for HPK1-interacting proteins that could regulate HPK1. We found that HPK1 interacted with Crk and CrkL adaptor proteins in vitro and in vivo and that the proline-rich motifs within HPK1 were involved in the differential interaction of HPK1 with the Crk proteins and Grb2. Crk and CrkL not only activated HPK1 but also synergized with HPK1 in the activation of JNK. The HPK1 mutant (HPK1-PR), which encodes the proline-rich region alone, blocked JNK activation by Crk and CrkL. Dominant-negative mutants of HPK1 downstream effectors, including MEKK1, TAK1, and SEK1, also inhibited Crk-induced JNK activation. These results suggest that the Crk proteins serve as upstream regulators of HPK1. We further observed that the HPK1 mutant HPK1-KD(M46), which encodes the kinase domain with a point mutation at lysine-46, and HPK1-PR blocked interleukin-2 (IL-2) induction in Jurkat T cells, suggesting that HPK1 signaling plays a critical role in IL-2 induction. Interestingly, HPK1 phosphorylated Crk and CrkL, mainly on serine and threonine residues in vitro. Taken together, our findings demonstrate the functional interaction of HPK1 with Crk and CrkL, reveal the downstream pathways of Crk- and CrkL-induced JNK activation, and highlight a potential role of HPK1 in T-cell activation.

MeSH Terms
Adaptor Proteins, Signal Transducing Amino Acid Sequence Animals COS Cells Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Line Enzyme Activation GRB2 Adaptor Protein Humans In Vitro Techniques Interleukin-2/biosynthesis JNK Mitogen-Activated Protein Kinases Jurkat Cells Lymphocyte Activation Mitogen-Activated Protein Kinases Mutation Nuclear Proteins/genetics,metabolism Protein Serine-Threonine Kinases/genetics,metabolism Proteins/genetics,metabolism Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-crk Recombinant Proteins/genetics,metabolism Signal Transduction T-Lymphocytes/immunology,metabolism
Chemicals
Adaptor Proteins, Signal Transducing CRKL protein GRB2 Adaptor Protein GRB2 protein, human Interleukin-2 Nuclear Proteins Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-crk Recombinant Proteins hematopoietic progenitor kinase 1 Protein Serine-Threonine Kinases Calcium-Calmodulin-Dependent Protein Kinases JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Ling P
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Yao Z
Meyer C F
Wang X S
Oehrl W
Feller S M
Tan T H
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.19.2.1359
Published
1999-02-00
Pages
1359-68
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC116064
Subset
IM
Grants
NIAID NIH HHS · R01-AI38649 · United States
NIAID NIH HHS · R01-AI42532 · United States
External Links
PubMed source DOI: 10.1128/MCB.19.2.1359 PMC Full Text View journal details
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