The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation

Pierre S W Lee, Yun Wang, Melissa G. Dominguez, Yee Guide Yeung, Maria A. Murphy, David D L Bowtell, E. Richard Stanley

Research output: Contribution to journalArticle

245 Citations (Scopus)

Abstract

Colony-stimulating factor-1 (CSF-1) activation of the CSF-1 receptor (CSF-1R) causes Cbl protooncoprotein tyrosine phosphorylation, Cbl-CSF-1R association and their simultaneous multiubiquitination at the plasma membrane. The CSF-1R is then rapidly internalized and degraded, whereas Cbl is deubiquitinated in the cytoplasm without being degraded. We have used primary macrophages from gene-targeted mice to study the role of Cbl. Cbl(-/-) macrophages form denser colonies and, at limiting CSF-1 concentrations, proliferate faster than Cbl(+/+) macrophages. Their CSF-1Rs fail to exhibit multiubiquitination and a second wave of tyrosine phosphorylation previously suggested to be involved in preparation of the CSF-1-CSF-1R complex for endocytosis. Consistent with this result, Cbl(-/-) macrophage cell surface CSF-1-CSF-1R complexes are internalized more slowly, yet are still lysosomally degraded, and the CSF-1 utilization by Cbl(-/-) macrophages is reduced ~ 2-fold. Thus, attenuation of proliferation by Cbl is associated with its positive regulation of the coordinated multiubiquitination and endocytosis of the activated CSF-1R, and a reduction in the time that the CSF-1R signals from the cell surface. The results provide a paradigm for studies of the mechanisms underlying Cbl attenuation of proliferative responses induced by ligation of receptor tyrosine kinases.

Original languageEnglish (US)
Pages (from-to)3616-3628
Number of pages13
JournalEMBO Journal
Volume18
Issue number13
DOIs
StatePublished - Jul 1 1999

Fingerprint

Colony-Stimulating Factor Receptors
Macrophage Colony-Stimulating Factor Receptors
Macrophage Colony-Stimulating Factor
Macrophages
Endocytosis
Phosphorylation
Tyrosine
Receptor Protein-Tyrosine Kinases
Cell membranes
Ligation
Cytoplasm
Genes
Chemical activation
Cell Membrane
Association reactions

Keywords

  • Cbl
  • Cell proliferation
  • CSF-1 receptor tyrosine kinase
  • Endocytosis
  • Multiubiquitination

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Lee, P. S. W., Wang, Y., Dominguez, M. G., Yeung, Y. G., Murphy, M. A., Bowtell, D. D. L., & Stanley, E. R. (1999). The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation. EMBO Journal, 18(13), 3616-3628. https://doi.org/10.1093/emboj/18.13.3616

The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation. / Lee, Pierre S W; Wang, Yun; Dominguez, Melissa G.; Yeung, Yee Guide; Murphy, Maria A.; Bowtell, David D L; Stanley, E. Richard.

In: EMBO Journal, Vol. 18, No. 13, 01.07.1999, p. 3616-3628.

Research output: Contribution to journalArticle

Lee, PSW, Wang, Y, Dominguez, MG, Yeung, YG, Murphy, MA, Bowtell, DDL & Stanley, ER 1999, 'The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation', EMBO Journal, vol. 18, no. 13, pp. 3616-3628. https://doi.org/10.1093/emboj/18.13.3616
Lee, Pierre S W ; Wang, Yun ; Dominguez, Melissa G. ; Yeung, Yee Guide ; Murphy, Maria A. ; Bowtell, David D L ; Stanley, E. Richard. / The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation. In: EMBO Journal. 1999 ; Vol. 18, No. 13. pp. 3616-3628.
@article{fbe1ab74b6e7468eb7bd9856275de15a,
title = "The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation",
abstract = "Colony-stimulating factor-1 (CSF-1) activation of the CSF-1 receptor (CSF-1R) causes Cbl protooncoprotein tyrosine phosphorylation, Cbl-CSF-1R association and their simultaneous multiubiquitination at the plasma membrane. The CSF-1R is then rapidly internalized and degraded, whereas Cbl is deubiquitinated in the cytoplasm without being degraded. We have used primary macrophages from gene-targeted mice to study the role of Cbl. Cbl(-/-) macrophages form denser colonies and, at limiting CSF-1 concentrations, proliferate faster than Cbl(+/+) macrophages. Their CSF-1Rs fail to exhibit multiubiquitination and a second wave of tyrosine phosphorylation previously suggested to be involved in preparation of the CSF-1-CSF-1R complex for endocytosis. Consistent with this result, Cbl(-/-) macrophage cell surface CSF-1-CSF-1R complexes are internalized more slowly, yet are still lysosomally degraded, and the CSF-1 utilization by Cbl(-/-) macrophages is reduced ~ 2-fold. Thus, attenuation of proliferation by Cbl is associated with its positive regulation of the coordinated multiubiquitination and endocytosis of the activated CSF-1R, and a reduction in the time that the CSF-1R signals from the cell surface. The results provide a paradigm for studies of the mechanisms underlying Cbl attenuation of proliferative responses induced by ligation of receptor tyrosine kinases.",
keywords = "Cbl, Cell proliferation, CSF-1 receptor tyrosine kinase, Endocytosis, Multiubiquitination",
author = "Lee, {Pierre S W} and Yun Wang and Dominguez, {Melissa G.} and Yeung, {Yee Guide} and Murphy, {Maria A.} and Bowtell, {David D L} and Stanley, {E. Richard}",
year = "1999",
month = "7",
day = "1",
doi = "10.1093/emboj/18.13.3616",
language = "English (US)",
volume = "18",
pages = "3616--3628",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "13",

}

TY - JOUR

T1 - The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation

AU - Lee, Pierre S W

AU - Wang, Yun

AU - Dominguez, Melissa G.

AU - Yeung, Yee Guide

AU - Murphy, Maria A.

AU - Bowtell, David D L

AU - Stanley, E. Richard

PY - 1999/7/1

Y1 - 1999/7/1

N2 - Colony-stimulating factor-1 (CSF-1) activation of the CSF-1 receptor (CSF-1R) causes Cbl protooncoprotein tyrosine phosphorylation, Cbl-CSF-1R association and their simultaneous multiubiquitination at the plasma membrane. The CSF-1R is then rapidly internalized and degraded, whereas Cbl is deubiquitinated in the cytoplasm without being degraded. We have used primary macrophages from gene-targeted mice to study the role of Cbl. Cbl(-/-) macrophages form denser colonies and, at limiting CSF-1 concentrations, proliferate faster than Cbl(+/+) macrophages. Their CSF-1Rs fail to exhibit multiubiquitination and a second wave of tyrosine phosphorylation previously suggested to be involved in preparation of the CSF-1-CSF-1R complex for endocytosis. Consistent with this result, Cbl(-/-) macrophage cell surface CSF-1-CSF-1R complexes are internalized more slowly, yet are still lysosomally degraded, and the CSF-1 utilization by Cbl(-/-) macrophages is reduced ~ 2-fold. Thus, attenuation of proliferation by Cbl is associated with its positive regulation of the coordinated multiubiquitination and endocytosis of the activated CSF-1R, and a reduction in the time that the CSF-1R signals from the cell surface. The results provide a paradigm for studies of the mechanisms underlying Cbl attenuation of proliferative responses induced by ligation of receptor tyrosine kinases.

AB - Colony-stimulating factor-1 (CSF-1) activation of the CSF-1 receptor (CSF-1R) causes Cbl protooncoprotein tyrosine phosphorylation, Cbl-CSF-1R association and their simultaneous multiubiquitination at the plasma membrane. The CSF-1R is then rapidly internalized and degraded, whereas Cbl is deubiquitinated in the cytoplasm without being degraded. We have used primary macrophages from gene-targeted mice to study the role of Cbl. Cbl(-/-) macrophages form denser colonies and, at limiting CSF-1 concentrations, proliferate faster than Cbl(+/+) macrophages. Their CSF-1Rs fail to exhibit multiubiquitination and a second wave of tyrosine phosphorylation previously suggested to be involved in preparation of the CSF-1-CSF-1R complex for endocytosis. Consistent with this result, Cbl(-/-) macrophage cell surface CSF-1-CSF-1R complexes are internalized more slowly, yet are still lysosomally degraded, and the CSF-1 utilization by Cbl(-/-) macrophages is reduced ~ 2-fold. Thus, attenuation of proliferation by Cbl is associated with its positive regulation of the coordinated multiubiquitination and endocytosis of the activated CSF-1R, and a reduction in the time that the CSF-1R signals from the cell surface. The results provide a paradigm for studies of the mechanisms underlying Cbl attenuation of proliferative responses induced by ligation of receptor tyrosine kinases.

KW - Cbl

KW - Cell proliferation

KW - CSF-1 receptor tyrosine kinase

KW - Endocytosis

KW - Multiubiquitination

UR - http://www.scopus.com/inward/record.url?scp=0033169024&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033169024&partnerID=8YFLogxK

U2 - 10.1093/emboj/18.13.3616

DO - 10.1093/emboj/18.13.3616

M3 - Article

VL - 18

SP - 3616

EP - 3628

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 13

ER -