PrPc activation induces neurite outgrowth and differentiation in PC12 cells: role for caveolin-1 in the signal transduction pathway.
Cellular prion protein (PrP(c)) is a ubiquitous glycoprotein, whose physiological role is poorly characterized. It has been suggested that PrP(c) participates in neuritogenesis, neuroprotection, copper metabolism, and signal transduction. In this study we detailed the intracellular events induced by PrP(c) antibody-mediated cross-linking in PC12 cells. We found a Fyn-dependent activation of the Ras-Raf pathway, which leads to a rapid and transient phosphorylation of extracellular regulated kinases. In addition, this activation cascade relies on the engagement of integrins, and involves focal adhesion kinase activation. We demonstrated the tyrosine phosphorylation of caveolin-1 as a consequence of PrP(c) stimulation, and showed that phosphocaveolin-1 scaffolds and coordinates protein complexes involved in PrP(c)-dependent signaling. Moreover, we found that caveolin-1 phosphorylation, is a mechanism for recruiting the C-terminal Src kinase and inactivating Fyn, so as to terminate cell signaling. Furthermore our data support a significant role for PrP(c) as a response mediator in neuritogenesis and cell differentiation.
Pantera
Barbara
B
Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Italy.
Bini
Chiara
C
Cirri
Paolo
P
Paoli
Paolo
P
Camici
Guido
G
Manao
Giampaolo
G
Caselli
Anna
A
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D051242:Caveolin 1 / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D018621:PrPC Proteins / Q000378:metabolism* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D051381:Rats; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D019061:src-Family Kinases
D051242:Caveolin 1; D016023:Integrins; D018621:PrPC Proteins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051416:Focal Adhesion Protein-Tyrosine Kinases; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins