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PMID:16014375

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Citation

Rucci, N, DiGiacinto, C, Orrù, L, Millimaggi, D, Baron, R and Teti, A (2005) A novel protein kinase C alpha-dependent signal to ERK1/2 activated by alphaVbeta3 integrin in osteoclasts and in Chinese hamster ovary (CHO) cells. J. Cell. Sci. 118:3263-75

Abstract

We identified a novel protein kinase C (PKC)alpha-dependent signal to extracellular signal-regulated kinase (ERK)1/2 in mouse osteoclasts and Chinese hamster ovary (CHO) cells, specifically activated by the alphaVbeta3 integrin. It involves translocation (i.e. activation) of PKCalpha from the cytosol to the membrane and/or the Triton X-100-insoluble subcellular fractions, with recruitment into a complex with alphaVbeta3 integrin, growth factor receptor-bound protein (Grb2), focal adhesion kinase (FAK) in CHO cells and proline-rich tyrosine kinase (PYK2) in osteoclasts. Engagement of alphavbeta3 integrin triggered ERK1/2 phosphorylation, but the underlying molecular mechanism was surprisingly independent of the well known Shc/Ras/Raf-1 cascade, and of phosphorylated MAP/ERK kinase (MEK)1/2, so far the only recognized direct activator of ERK1/2. In contrast, PKCalpha was involved in ERK1/2 activation because inhibition of its activity prevented ERK1/2 phosphorylation. The tyrosine kinase c-Src also contributed to ERK1/2 activation, however, it did not interact with PKCalpha in the same molecular complex. The alphaVbeta3/PKCalpha complex formation was fully dependent upon the intracellular calcium concentration ([Ca2+]i), and the use of the intracellular Ca2+ chelator 1,2-bis(o-amino-phenoxy)ethane-N,N,N',N'-tetraaceticacidtetra (acetoxymethyl) ester (BAPTA-AM) also inhibited PKCalpha translocation and ERK1/2 phosphorylation. Functional studies showed that alphaVbeta3 integrin-activated PKCalpha was involved in cell migration and osteoclast bone resorption, but had no effect on the ability of cells to attach to LM609, suggesting a role in events downstream of alphaVbeta3 integrin engagement.

Links

PubMed Online version:10.1242/jcs.02436

Keywords

Animals; Antibodies, Monoclonal/pharmacology; Bone Resorption/metabolism; CHO Cells; Calcium/physiology; Carbazoles/pharmacology; Cell Movement/drug effects; Cell Movement/physiology; Cricetinae; Cricetulus; Indoles/pharmacology; Integrin alphaVbeta3/drug effects; Integrin alphaVbeta3/physiology; Mice; Mitogen-Activated Protein Kinase 1/drug effects; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/drug effects; Mitogen-Activated Protein Kinase 3/metabolism; Osteoclasts/cytology; Osteoclasts/drug effects; Osteoclasts/metabolism; Phosphorylation; Protein-Tyrosine Kinases/physiology; Signal Transduction/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ITB3

enables

GO:0005080: protein kinase C binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P20444

F

  • occurs_in:(CL:0000092)

Seeded From UniProt

complete

MOUSE:ITB3

part_of

GO:0035866: alphav-beta3 integrin-PKCalpha complex

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000092)

Seeded From UniProt

complete

HUMAN:ITB3

part_of

GO:0035866: alphav-beta3 integrin-PKCalpha complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ITAV

part_of

GO:0035866: alphav-beta3 integrin-PKCalpha complex

ECO:0000303: author statement without traceable support used in manual assertion

C

Seeded From UniProt

complete

MOUSE:KPCA

enables

GO:0005178: integrin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O54890

F

  • occurs_in:(CL:0000092)

Seeded From UniProt

complete

MOUSE:KPCA

part_of

GO:0035866: alphav-beta3 integrin-PKCalpha complex

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000092)

Seeded From UniProt

complete

MOUSE:KPCA

involved_in

GO:0045780: positive regulation of bone resorption

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000092)

Seeded From UniProt

complete

MOUSE:ITAV

contributes_to

GO:0005080: protein kinase C binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ITAV

involved_in

GO:0051209: release of sequestered calcium ion into cytosol

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ITAV

involved_in

GO:0070371: ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ITAV

involved_in

GO:0045124: regulation of bone resorption

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KPCA

part_of

GO:0035866: alphav-beta3 integrin-PKCalpha complex

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000092)

Seeded From UniProt

complete

MOUSE:KPCA

enables

GO:0005178: integrin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O54890

F

occurs_in:(CL:0000092)

Seeded From UniProt

complete

MOUSE:KPCA

involved_in

GO:0045780: positive regulation of bone resorption

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0000092)

Seeded From UniProt

complete


See also

References

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