Chondroitin sulfate proteoglycan 4 enhanced melanoma motility and growth requires a cysteine in the core protein transmembrane domain

Jianbo Yang, Matthew A. Price, Leah E.C. Wanshura, Jinsong He, Mei Yi, Danny R. Welch, Guiyuan Li, Sean Conner, Jonathan Sachs, Eva A. Turley, James B. McCarthy

Research output: Contribution to journalArticle

Abstract

Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan that enhances malignant potential in melanoma and several other tumor types. CSPG4 functions as a transmembrane scaffold in melanoma cells to activate oncogenic signaling pathways such as focal adhesion kinase (FAK) and extracellular signal regulated kinases 1,2, that control motility, invasion and anchorage independent growth. Here, we demonstrate that CSPG4 promotes directional motility and anchorage independent growth of melanoma cells by organizing and positioning a signaling complex containing activated FAK to lipid rafts within the plasma membrane of migrating cells. This FAK-containing signal transduction platform, which consists of syntenin-1, active Src and caveolin-1 requires the cytoplasmic domain of CSPG4 for assembly. Enhanced directional motility promoted by this complex also requires a CSPG4 transmembrane cysteine residue C2230. Substituting C2230 with alanine (CSPG4) still permits assembly of the signaling complex, however Src remains in an inactive state. CSPG4 also fails to promote anchorage independent growth and activation of extracellular signal regulated kinases 1,2. Therapies that target the transmembrane domain of CSPG4 could be a novel strategy for limiting progression by disrupting its function as a compartmentalized motogenic and growth-promoting oncogenic signaling node.

Original languageEnglish (US)
Pages (from-to)365-375
Number of pages11
JournalMelanoma research
Volume29
Issue number4
DOIs
StatePublished - Aug 1 2019

Fingerprint

Cysteine
Melanoma
Growth
Focal Adhesion Protein-Tyrosine Kinases
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Syntenins
Caveolin 1
Protein Domains
chondroitin sulfate proteoglycan 4
Proteoglycans
Alanine
Signal Transduction
Cell Membrane
Lipids
Neoplasms

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Chondroitin sulfate proteoglycan 4 enhanced melanoma motility and growth requires a cysteine in the core protein transmembrane domain. / Yang, Jianbo; Price, Matthew A.; Wanshura, Leah E.C.; He, Jinsong; Yi, Mei; Welch, Danny R.; Li, Guiyuan; Conner, Sean; Sachs, Jonathan; Turley, Eva A.; McCarthy, James B.

In: Melanoma research, Vol. 29, No. 4, 01.08.2019, p. 365-375.

Research output: Contribution to journalArticle

Yang, Jianbo ; Price, Matthew A. ; Wanshura, Leah E.C. ; He, Jinsong ; Yi, Mei ; Welch, Danny R. ; Li, Guiyuan ; Conner, Sean ; Sachs, Jonathan ; Turley, Eva A. ; McCarthy, James B. / Chondroitin sulfate proteoglycan 4 enhanced melanoma motility and growth requires a cysteine in the core protein transmembrane domain. In: Melanoma research. 2019 ; Vol. 29, No. 4. pp. 365-375.
@article{26e6b4b5d4844deeac615f57bf1da238,
title = "Chondroitin sulfate proteoglycan 4 enhanced melanoma motility and growth requires a cysteine in the core protein transmembrane domain",
abstract = "Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan that enhances malignant potential in melanoma and several other tumor types. CSPG4 functions as a transmembrane scaffold in melanoma cells to activate oncogenic signaling pathways such as focal adhesion kinase (FAK) and extracellular signal regulated kinases 1,2, that control motility, invasion and anchorage independent growth. Here, we demonstrate that CSPG4 promotes directional motility and anchorage independent growth of melanoma cells by organizing and positioning a signaling complex containing activated FAK to lipid rafts within the plasma membrane of migrating cells. This FAK-containing signal transduction platform, which consists of syntenin-1, active Src and caveolin-1 requires the cytoplasmic domain of CSPG4 for assembly. Enhanced directional motility promoted by this complex also requires a CSPG4 transmembrane cysteine residue C2230. Substituting C2230 with alanine (CSPG4) still permits assembly of the signaling complex, however Src remains in an inactive state. CSPG4 also fails to promote anchorage independent growth and activation of extracellular signal regulated kinases 1,2. Therapies that target the transmembrane domain of CSPG4 could be a novel strategy for limiting progression by disrupting its function as a compartmentalized motogenic and growth-promoting oncogenic signaling node.",
author = "Jianbo Yang and Price, {Matthew A.} and Wanshura, {Leah E.C.} and Jinsong He and Mei Yi and Welch, {Danny R.} and Guiyuan Li and Sean Conner and Jonathan Sachs and Turley, {Eva A.} and McCarthy, {James B.}",
year = "2019",
month = "8",
day = "1",
doi = "10.1097/CMR.0000000000000574",
language = "English (US)",
volume = "29",
pages = "365--375",
journal = "Melanoma Research",
issn = "0960-8931",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Chondroitin sulfate proteoglycan 4 enhanced melanoma motility and growth requires a cysteine in the core protein transmembrane domain

AU - Yang, Jianbo

AU - Price, Matthew A.

AU - Wanshura, Leah E.C.

AU - He, Jinsong

AU - Yi, Mei

AU - Welch, Danny R.

AU - Li, Guiyuan

AU - Conner, Sean

AU - Sachs, Jonathan

AU - Turley, Eva A.

AU - McCarthy, James B.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan that enhances malignant potential in melanoma and several other tumor types. CSPG4 functions as a transmembrane scaffold in melanoma cells to activate oncogenic signaling pathways such as focal adhesion kinase (FAK) and extracellular signal regulated kinases 1,2, that control motility, invasion and anchorage independent growth. Here, we demonstrate that CSPG4 promotes directional motility and anchorage independent growth of melanoma cells by organizing and positioning a signaling complex containing activated FAK to lipid rafts within the plasma membrane of migrating cells. This FAK-containing signal transduction platform, which consists of syntenin-1, active Src and caveolin-1 requires the cytoplasmic domain of CSPG4 for assembly. Enhanced directional motility promoted by this complex also requires a CSPG4 transmembrane cysteine residue C2230. Substituting C2230 with alanine (CSPG4) still permits assembly of the signaling complex, however Src remains in an inactive state. CSPG4 also fails to promote anchorage independent growth and activation of extracellular signal regulated kinases 1,2. Therapies that target the transmembrane domain of CSPG4 could be a novel strategy for limiting progression by disrupting its function as a compartmentalized motogenic and growth-promoting oncogenic signaling node.

AB - Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan that enhances malignant potential in melanoma and several other tumor types. CSPG4 functions as a transmembrane scaffold in melanoma cells to activate oncogenic signaling pathways such as focal adhesion kinase (FAK) and extracellular signal regulated kinases 1,2, that control motility, invasion and anchorage independent growth. Here, we demonstrate that CSPG4 promotes directional motility and anchorage independent growth of melanoma cells by organizing and positioning a signaling complex containing activated FAK to lipid rafts within the plasma membrane of migrating cells. This FAK-containing signal transduction platform, which consists of syntenin-1, active Src and caveolin-1 requires the cytoplasmic domain of CSPG4 for assembly. Enhanced directional motility promoted by this complex also requires a CSPG4 transmembrane cysteine residue C2230. Substituting C2230 with alanine (CSPG4) still permits assembly of the signaling complex, however Src remains in an inactive state. CSPG4 also fails to promote anchorage independent growth and activation of extracellular signal regulated kinases 1,2. Therapies that target the transmembrane domain of CSPG4 could be a novel strategy for limiting progression by disrupting its function as a compartmentalized motogenic and growth-promoting oncogenic signaling node.

UR - http://www.scopus.com/inward/record.url?scp=85069237161&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069237161&partnerID=8YFLogxK

U2 - 10.1097/CMR.0000000000000574

DO - 10.1097/CMR.0000000000000574

M3 - Article

C2 - 31140988

AN - SCOPUS:85069237161

VL - 29

SP - 365

EP - 375

JO - Melanoma Research

JF - Melanoma Research

SN - 0960-8931

IS - 4

ER -