Protein kinase C and rho activated coiled coil protein kinase 2 (ROCK2) modulate Alzheimer's APP metabolism and phosphorylation of the Vps10-domain protein, SorL1

Rachel F. Lane, Joshua W. Gatson, Scott A. Small, Michelle E. Ehrlich, Sam Gandy

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: Generation of the amyloid (A) peptide of Alzheimer's disease (AD) is differentially regulated through the intracellular trafficking of the amyloid precursor protein (APP) within the secretory and endocytic pathways. Protein kinase C (PKC) and rho-activated coiled-coil kinases (ROCKs) are two "third messenger" signaling molecules that control the relative utilization of these two pathways. Several members of the Vps family of receptors (Vps35, SorL1, SorCS1) play important roles in post-trans-Golgi network (TGN) sorting and generation of APP derivatives, including A at the TGN, endosome and the plasma membrane. We now report that Vps10-domain proteins are candidate substrates for PKC and/or ROCK2 and act as phospho-state-sensitive physiological effectors for post-TGN sorting of APP and its derivatives. Results: Analysis of the SorL1 cytoplasmic tail revealed multiple consensus sites for phosphorylation by protein kinases. SorL1 was subsequently identified as a phosphoprotein, based on sensitivity of its electrophoretic migration pattern to calf intestine alkaline phosphatase and on its reaction with anti-phospho-serine antibodies. Activation of PKC resulted in increased shedding of the ectodomains of both APP and SorL1, and this was paralleled by an apparent increase in the level of the phosphorylated form of SorL1. ROCK2, the neuronal isoform of another protein kinase, was found to form complexes with SorL1, and both ROCK2 inhibition and ROCK2 knockdown enhanced generation of both soluble APP and A. Conclusion: These results highlight the potential importance of SorL1 in elucidating phospho-state sensitive mechanisms in the regulation of metabolism of APP and A by PKC and ROCK2.

Original languageEnglish (US)
Article number62
JournalMolecular Neurodegeneration
Volume5
Issue number1
DOIs
StatePublished - 2010

Fingerprint

Amyloid beta-Protein Precursor
Protein Kinases
Protein Kinase C
Serum Amyloid A Protein
Phosphorylation
trans-Golgi Network
Secretory Pathway
Endosomes
Phosphoproteins
Amyloid
Serine
Intestines
Alkaline Phosphatase
Protein Domains
Alzheimer Disease
Protein Isoforms
Phosphotransferases
Cell Membrane
Peptides
Antibodies

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Protein kinase C and rho activated coiled coil protein kinase 2 (ROCK2) modulate Alzheimer's APP metabolism and phosphorylation of the Vps10-domain protein, SorL1. / Lane, Rachel F.; Gatson, Joshua W.; Small, Scott A.; Ehrlich, Michelle E.; Gandy, Sam.

In: Molecular Neurodegeneration, Vol. 5, No. 1, 62, 2010.

Research output: Contribution to journalArticle

@article{b9ab11c236274dac9bca1e86bffcb23d,
title = "Protein kinase C and rho activated coiled coil protein kinase 2 (ROCK2) modulate Alzheimer's APP metabolism and phosphorylation of the Vps10-domain protein, SorL1",
abstract = "Background: Generation of the amyloid (A) peptide of Alzheimer's disease (AD) is differentially regulated through the intracellular trafficking of the amyloid precursor protein (APP) within the secretory and endocytic pathways. Protein kinase C (PKC) and rho-activated coiled-coil kinases (ROCKs) are two {"}third messenger{"} signaling molecules that control the relative utilization of these two pathways. Several members of the Vps family of receptors (Vps35, SorL1, SorCS1) play important roles in post-trans-Golgi network (TGN) sorting and generation of APP derivatives, including A at the TGN, endosome and the plasma membrane. We now report that Vps10-domain proteins are candidate substrates for PKC and/or ROCK2 and act as phospho-state-sensitive physiological effectors for post-TGN sorting of APP and its derivatives. Results: Analysis of the SorL1 cytoplasmic tail revealed multiple consensus sites for phosphorylation by protein kinases. SorL1 was subsequently identified as a phosphoprotein, based on sensitivity of its electrophoretic migration pattern to calf intestine alkaline phosphatase and on its reaction with anti-phospho-serine antibodies. Activation of PKC resulted in increased shedding of the ectodomains of both APP and SorL1, and this was paralleled by an apparent increase in the level of the phosphorylated form of SorL1. ROCK2, the neuronal isoform of another protein kinase, was found to form complexes with SorL1, and both ROCK2 inhibition and ROCK2 knockdown enhanced generation of both soluble APP and A. Conclusion: These results highlight the potential importance of SorL1 in elucidating phospho-state sensitive mechanisms in the regulation of metabolism of APP and A by PKC and ROCK2.",
author = "Lane, {Rachel F.} and Gatson, {Joshua W.} and Small, {Scott A.} and Ehrlich, {Michelle E.} and Sam Gandy",
year = "2010",
doi = "10.1186/1750-1326-5-62",
language = "English (US)",
volume = "5",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Protein kinase C and rho activated coiled coil protein kinase 2 (ROCK2) modulate Alzheimer's APP metabolism and phosphorylation of the Vps10-domain protein, SorL1

AU - Lane, Rachel F.

AU - Gatson, Joshua W.

AU - Small, Scott A.

AU - Ehrlich, Michelle E.

AU - Gandy, Sam

PY - 2010

Y1 - 2010

N2 - Background: Generation of the amyloid (A) peptide of Alzheimer's disease (AD) is differentially regulated through the intracellular trafficking of the amyloid precursor protein (APP) within the secretory and endocytic pathways. Protein kinase C (PKC) and rho-activated coiled-coil kinases (ROCKs) are two "third messenger" signaling molecules that control the relative utilization of these two pathways. Several members of the Vps family of receptors (Vps35, SorL1, SorCS1) play important roles in post-trans-Golgi network (TGN) sorting and generation of APP derivatives, including A at the TGN, endosome and the plasma membrane. We now report that Vps10-domain proteins are candidate substrates for PKC and/or ROCK2 and act as phospho-state-sensitive physiological effectors for post-TGN sorting of APP and its derivatives. Results: Analysis of the SorL1 cytoplasmic tail revealed multiple consensus sites for phosphorylation by protein kinases. SorL1 was subsequently identified as a phosphoprotein, based on sensitivity of its electrophoretic migration pattern to calf intestine alkaline phosphatase and on its reaction with anti-phospho-serine antibodies. Activation of PKC resulted in increased shedding of the ectodomains of both APP and SorL1, and this was paralleled by an apparent increase in the level of the phosphorylated form of SorL1. ROCK2, the neuronal isoform of another protein kinase, was found to form complexes with SorL1, and both ROCK2 inhibition and ROCK2 knockdown enhanced generation of both soluble APP and A. Conclusion: These results highlight the potential importance of SorL1 in elucidating phospho-state sensitive mechanisms in the regulation of metabolism of APP and A by PKC and ROCK2.

AB - Background: Generation of the amyloid (A) peptide of Alzheimer's disease (AD) is differentially regulated through the intracellular trafficking of the amyloid precursor protein (APP) within the secretory and endocytic pathways. Protein kinase C (PKC) and rho-activated coiled-coil kinases (ROCKs) are two "third messenger" signaling molecules that control the relative utilization of these two pathways. Several members of the Vps family of receptors (Vps35, SorL1, SorCS1) play important roles in post-trans-Golgi network (TGN) sorting and generation of APP derivatives, including A at the TGN, endosome and the plasma membrane. We now report that Vps10-domain proteins are candidate substrates for PKC and/or ROCK2 and act as phospho-state-sensitive physiological effectors for post-TGN sorting of APP and its derivatives. Results: Analysis of the SorL1 cytoplasmic tail revealed multiple consensus sites for phosphorylation by protein kinases. SorL1 was subsequently identified as a phosphoprotein, based on sensitivity of its electrophoretic migration pattern to calf intestine alkaline phosphatase and on its reaction with anti-phospho-serine antibodies. Activation of PKC resulted in increased shedding of the ectodomains of both APP and SorL1, and this was paralleled by an apparent increase in the level of the phosphorylated form of SorL1. ROCK2, the neuronal isoform of another protein kinase, was found to form complexes with SorL1, and both ROCK2 inhibition and ROCK2 knockdown enhanced generation of both soluble APP and A. Conclusion: These results highlight the potential importance of SorL1 in elucidating phospho-state sensitive mechanisms in the regulation of metabolism of APP and A by PKC and ROCK2.

UR - http://www.scopus.com/inward/record.url?scp=78650627732&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650627732&partnerID=8YFLogxK

U2 - 10.1186/1750-1326-5-62

DO - 10.1186/1750-1326-5-62

M3 - Article

VL - 5

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

SN - 1750-1326

IS - 1

M1 - 62

ER -