Salzano, Marcella
(2011)
Mechanism of regulation of Raf-1 by Ca2+/Calmodulin-dependent kinase II.
[Tesi di dottorato]
(Unpublished)
Item Type: |
Tesi di dottorato
|
Resource language: |
English |
Title: |
Mechanism of regulation of Raf-1 by Ca2+/Calmodulin-dependent kinase II |
Creators: |
Creators | Email |
---|
Salzano, Marcella | salzanomarcella@hotmail.it |
|
Date: |
29 November 2011 |
Number of Pages: |
51 |
Institution: |
Università degli Studi di Napoli Federico II |
Department: |
Biologia e patologia cellullare e molecolare "L. Califano" |
Scuola di dottorato: |
Medicina molecolare |
Dottorato: |
Patologia e fisiopatologia molecolare |
Ciclo di dottorato: |
24 |
Coordinatore del Corso di dottorato: |
nome | email |
---|
Avvedimento, Vittorio Enrico | avvedim@unina.it |
|
Tutor: |
nome | email |
---|
Vitale, Mario | mavitale@unisa.it |
|
Date: |
29 November 2011 |
Number of Pages: |
51 |
Keywords: |
CaMKII; Raf-1; oncogenic Ras |
Settori scientifico-disciplinari del MIUR: |
Area 06 - Scienze mediche > MED/04 - Patologia generale |
[error in script]
[error in script]
Date Deposited: |
13 Dec 2011 11:32 |
Last Modified: |
30 Apr 2014 19:47 |
URI: |
http://www.fedoa.unina.it/id/eprint/8666 |
DOI: |
10.6092/UNINA/FEDOA/8666 |
Collection description
The calcium-calmodulin dependent kinase II (CaMKII) is an ubiquitous serine/threonine protein kinase involved in multiple signalings and biological functions. It has been demonstrated that in epithelial and mesenchimal cells CaMKII participates with Ras to Raf-1 activation and that it is necessary for ERK activation by diverse factors. Raf-1 activation is complex. Maximal Raf-1 activation is reached by phosphorylation at Y341 by Src and at S338. Although early data proposed the involvement of p21-activated kinase 3 (Pak3), the kinase phosphorylating S338 is not definitively identified.
Aim of my thesis is to go more insight into the molecular mechanisms of CaMKII/Raf-1 interaction and to verify the hypothesis that CaMKII phosphorylates Raf-1 at Ser338. To this purpose, I investigated the role of CaMKII in Raf-1 and ERK activation by oncogenic Ras and other factors, in COS-7 and NIH3T3 cells. Serum, SrcY527 and RasV12 activated CaMKII. CaMKII was necessary for Raf-1 and ERK activation by all these factors. CaMKII was necessary to the phosphorylation of S338 Raf-1 by serum, fibronectin or oncogenic Ras. Conversely, the inhibition of phosphatidylinositol 3-kinase, which in turn activates Pak3, was ineffective. The direct kinase activity of CaMKII on the serine 338 residue, was demonstrated in vitro by interaction of purified kinases.
These results demonstrate that CaMKII phosphorylates Raf-1 at S338 and partecipates to ERK activation upon different physiologic and pathologic stimuli in the MAPK cascade. This kinase, might have a role in cancers harbouring oncogenic Ras and could represent a new therapeutic target for pharmacological intervention in these tumors.
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