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Molecular mechanisms underlying morphological effects of protein kinase C under normal conditions and cellular stress.

Sunesson, Lovisa LU (2008) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2008:115.
Abstract
The protein kinase C (PKC) family of serine/threonine kinases consists of 10-15 members. The PKC isoforms have central roles in many essential cellular processes, including proliferation, apoptosis, differentiation, cytoskeletal changes, and migration. The PKC family can be subgrouped into classical, novel and atypical isoforms depending on structure and sensitivity to the activators diacylglycerol, phorbol esters and Ca2+.



We have previously reported of a neurite-inducing effect specific for PKCε, a novel PKC isoform. The effect has been shown to be mediated through the regulatory domain and independently of the catalytic activity of PKCε. Here we identify residues located in the base of the C1b domain important for... (More)
The protein kinase C (PKC) family of serine/threonine kinases consists of 10-15 members. The PKC isoforms have central roles in many essential cellular processes, including proliferation, apoptosis, differentiation, cytoskeletal changes, and migration. The PKC family can be subgrouped into classical, novel and atypical isoforms depending on structure and sensitivity to the activators diacylglycerol, phorbol esters and Ca2+.



We have previously reported of a neurite-inducing effect specific for PKCε, a novel PKC isoform. The effect has been shown to be mediated through the regulatory domain and independently of the catalytic activity of PKCε. Here we identify residues located in the base of the C1b domain important for the neurite-inducing effect of PKCε. We have in an approach to elucidate the mechanisms that mediate PKCε-induced neurite outgrowth performed a screening for proteins that interact with the most potent neurite-inducing PKCε construct. We have identified several novel PKCε-interacting proteins, including the intermediate filament peripherin and several mRNA-binding proteins. Peripherin and three RNA-binding proteins G3BP2, PABPC1, and IGF2BP3 were further investigated regarding their putative function in PKCε-mediated neurite outgrowth. However, no involvement could be detected for any of the investigated interacting proteins. Interactions between peripherin, G3BP2, PABPC1, or IGF2BP3 and PKCε have been confirmed for endogenous proteins. The peripherin-PKCε interaction is mediated by the C1b domain. We have found that PKCε induces peripherin aggregation when the expression levels of peripherin are elevated and that an activation of PKC induces apoptosis of cells overexpressing peripherin. These novel findings can be of importance in understanding the mechanism behind the neurodegenerative disease amyotrophic lateral sclerosis (ALS), where aggregates containing peripherin are essentially always seen in afflicted tissues. The RNA-binding proteins were found to localize to specific RNA-granules, formed when cells are exposed to stress. PKCalpha, rather than PKCε, was found to be the main PKC isoform found in these stress granules. We have furthermore discovered a role for PKCalpha in regulating stress granule formation. (Less)
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author
supervisor
opponent
  • Ivaska, Johanna, University of Turku and VTT Biotechnology Centre, Turku, Finland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
neuroblastoma, amytrophic lateral sclerosis, PABPC1, IGF2BP3, G3BP2, peripherin, C1 domain, protein-protein-interactions, Protein kinase C, neurite outgrowth
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2008:115
pages
112 pages
publisher
Lund University, Faculty of Medicine
defense location
Main Lecture Hall, Pathology building, entrance 78, UMAS, Malmö
defense date
2008-12-05 09:00
ISSN
1652-8220
ISBN
978-91-86059-68-2
language
English
LU publication?
yes
id
ec3ca8ee-0c50-4bf0-ae05-bdc63b9b70bd (old id 1266237)
date added to LUP
2008-11-19 13:50:13
date last changed
2016-09-19 08:44:49
@phdthesis{ec3ca8ee-0c50-4bf0-ae05-bdc63b9b70bd,
  abstract     = {The protein kinase C (PKC) family of serine/threonine kinases consists of 10-15 members. The PKC isoforms have central roles in many essential cellular processes, including proliferation, apoptosis, differentiation, cytoskeletal changes, and migration. The PKC family can be subgrouped into classical, novel and atypical isoforms depending on structure and sensitivity to the activators diacylglycerol, phorbol esters and Ca2+. <br/><br>
<br/><br>
We have previously reported of a neurite-inducing effect specific for PKCε, a novel PKC isoform. The effect has been shown to be mediated through the regulatory domain and independently of the catalytic activity of PKCε. Here we identify residues located in the base of the C1b domain important for the neurite-inducing effect of PKCε. We have in an approach to elucidate the mechanisms that mediate PKCε-induced neurite outgrowth performed a screening for proteins that interact with the most potent neurite-inducing PKCε construct. We have identified several novel PKCε-interacting proteins, including the intermediate filament peripherin and several mRNA-binding proteins. Peripherin and three RNA-binding proteins G3BP2, PABPC1, and IGF2BP3 were further investigated regarding their putative function in PKCε-mediated neurite outgrowth. However, no involvement could be detected for any of the investigated interacting proteins. Interactions between peripherin, G3BP2, PABPC1, or IGF2BP3 and PKCε have been confirmed for endogenous proteins. The peripherin-PKCε interaction is mediated by the C1b domain. We have found that PKCε induces peripherin aggregation when the expression levels of peripherin are elevated and that an activation of PKC induces apoptosis of cells overexpressing peripherin. These novel findings can be of importance in understanding the mechanism behind the neurodegenerative disease amyotrophic lateral sclerosis (ALS), where aggregates containing peripherin are essentially always seen in afflicted tissues. The RNA-binding proteins were found to localize to specific RNA-granules, formed when cells are exposed to stress. PKCalpha, rather than PKCε, was found to be the main PKC isoform found in these stress granules. We have furthermore discovered a role for PKCalpha in regulating stress granule formation.},
  author       = {Sunesson, Lovisa},
  isbn         = {978-91-86059-68-2},
  issn         = {1652-8220},
  keyword      = {neuroblastoma,amytrophic lateral sclerosis,PABPC1,IGF2BP3,G3BP2,peripherin,C1 domain,protein-protein-interactions,Protein kinase C,neurite outgrowth},
  language     = {eng},
  pages        = {112},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Molecular mechanisms underlying morphological effects of protein kinase C under normal conditions and cellular stress.},
  volume       = {2008:115},
  year         = {2008},
}