Specific regulation of noncanonical p38alpha activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte

Circ Res. 2010 Apr 30;106(8):1404-12. doi: 10.1161/CIRCRESAHA.109.213769. Epub 2010 Mar 18.


Rationale: p38 is an important stress activated protein kinase involved in gene regulation, proliferation, differentiation, and cell death regulation in heart. p38 kinase activity can be induced through canonical pathway via upstream kinases or by noncanonical autophosphorylation. The intracellular p38 kinase activity is tightly regulated and maintained at low level under basal condition. The underlying regulatory mechanism for canonical p38 kinase activation is well-studied, but the regulation of noncanonical p38 autophosphorylation remains poorly understood.

Objective: We investigated the molecular basis for the regulation of noncanonical p38 autophosphorylation and its potential functional impact in cardiomyocytes.

Methods and results: Using both proteomic and biochemical tools, we established that heat shock protein (Hsp)90-Cdc37 chaperones are part of the p38alpha signaling complex in mammalian cells both in vitro and in vivo. The Hsp90-Cdc37 chaperone complex interacts with p38 via direct binding between p38 and Cdc37. Cdc37 expression is both sufficient and necessary to suppress noncanonical p38 activation via autophosphorylation at either basal state or under TAB1 (TAK1 binding protein-1) induction. In contrast, Cdc37 expression has no impact on p38 activation by canonical upstream kinase MKK3 or oxidative stress. Furthermore, Hsp90 inhibition results in p38 activation via autophosphorylation, and p38 activity contribute to apoptotic cell death induced by Hsp90 inhibition.

Conclusion: Our study has revealed a so far uncharacterized function of Hsp90-Cdc37 as an endogenous regulator of noncanonical p38 activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis
  • Benzoquinones / pharmacology
  • COS Cells
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Survival
  • Chaperonins / genetics
  • Chaperonins / metabolism*
  • Chlorocebus aethiops
  • Enzyme Activation
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Lactams, Macrocyclic / pharmacology
  • MAP Kinase Kinase 3 / metabolism
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 14 / genetics
  • Mitogen-Activated Protein Kinase 14 / metabolism*
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Multiprotein Complexes
  • Mutation
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology*
  • Oxidative Stress
  • Phosphorylation
  • Protein Binding
  • RNA Interference
  • Rats
  • Recombinant Proteins / metabolism
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • Time Factors
  • Transfection


  • Adaptor Proteins, Signal Transducing
  • Benzoquinones
  • CDC37 protein, human
  • Cdc37 protein, mouse
  • Cell Cycle Proteins
  • HSP90 Heat-Shock Proteins
  • Hspca protein, mouse
  • Lactams, Macrocyclic
  • Molecular Chaperones
  • Multiprotein Complexes
  • Recombinant Proteins
  • tanespimycin
  • Mitogen-Activated Protein Kinase 14
  • MAP Kinase Kinase 3
  • Chaperonins
  • geldanamycin