Document Detail

Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation.
MedLine Citation:
PMID:  17024227     Owner:  NLM     Status:  MEDLINE    
We studied monocytic differentiation of primary mouse progenitor cells to understand molecular mechanisms of differentiation. We found a tightly controlled non-apoptotic activation of caspase-3 that correlated with differentiation. Although caspase activity was already detected during monocytic differentiation, a caspase-3 target has not been identified yet. We show that hematopoietic progenitor kinase 1 (HPK1) is processed towards its N- and C-terminal fragments during monocytic differentiation. While HPK1 is an immunoreceptor-proximal kinase in T and B cells, its role in myeloid cells is elusive. Here, we show that the N-terminal cleavage product, HPK1-N, comprising the kinase domain, confers progenitor cell survival independent of the growth factor IL-3. Furthermore, HPK1-N causes differentiation of progenitor cells towards the monocytic lineage. In contrast to full-length kinase, HPK1-N is constitutively active causing sustained JNK activation, Bad phosphorylation and survival. Blocking of caspase activity during differentiation of primary mouse progenitor cells leads to reduced HPK1-N levels, suppressed JNK activity and attenuated monocytic differentiation. Our work explains growth factor-independent survival during monocytic differentiation by caspase-mediated processing of HPK1 towards HPK1-N.
R Arnold; C R Frey; W Müller; D Brenner; P H Krammer; F Kiefer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-10-06
Journal Detail:
Title:  Cell death and differentiation     Volume:  14     ISSN:  1350-9047     ISO Abbreviation:  Cell Death Differ.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-02-15     Completed Date:  2007-06-08     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9437445     Medline TA:  Cell Death Differ     Country:  England    
Other Details:
Languages:  eng     Pagination:  568-75     Citation Subset:  IM    
Max-Planck-Institute for Physiological and Clinical Research, WG Kerckhoff-Institute, Parkstrasse 1, D-61231 Bad Nauheim, Germany.
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MeSH Terms
Caspase 3 / metabolism
Cell Differentiation
Cell Survival
Cells, Cultured
Enzyme Activation
Gene Expression Regulation, Enzymologic
Interleukin-3 / pharmacology*
JNK Mitogen-Activated Protein Kinases / metabolism*
Monocytes / metabolism,  physiology*
Protein-Serine-Threonine Kinases / genetics,  metabolism*
Signal Transduction*
Stem Cells / physiology
bcl-Associated Death Protein / metabolism
Reg. No./Substance:
0/Interleukin-3; 0/bcl-Associated Death Protein; EC progenitor kinase 1; EC Kinases; EC Mitogen-Activated Protein Kinases; EC 3.4.22.-/Caspase 3

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