Competitive binding of Rab21 and p120RasGAP to integrins regulates receptor traffic and migration

Anja Mai, Stefan Veltel, Teijo Pellinen, Artur Padzik, Eleanor Coffey, Varpu Marjomäki, Johanna Ivaska

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Abstract

Integrin trafficking from and to the plasma membrane controls many aspects of cell behavior including cell motility, invasion, and cytokinesis. Recruitment of integrin cargo to the endocytic machinery is regulated by the small GTPase Rab21, but the detailed molecular mechanisms underlying integrin cargo recruitment are yet unknown. Here we identify an important role for p120RasGAP (RASA1) in the recycling of endocytosed α/β1-integrin heterodimers to the plasma membrane. Silencing of p120RasGAP attenuated integrin recycling and augmented cell motility. Mechanistically, p120RasGAP interacted with the cytoplasmic domain of integrin α-subunits via its GAP domain and competed with Rab21 for binding to endocytosed integrins. This in turn facilitated exit of the integrin from Rab21- and EEA1-positive endosomes to drive recycling. Our results assign an unexpected role for p120RasGAP in the regulation of integrin traffic in cancer cells and reveal a new concept of competitive binding of Rab GTPases and GAP proteins to receptors as a regulatory mechanism in trafficking.
Original languageEnglish
Pages (from-to)291-306
JournalJournal of Cell Biology
Volume194
Issue number2
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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p120 GTPase Activating Protein
Competitive Binding
Integrins
Recycling
Endocytosis
Cell Movement
rab GTP-Binding Proteins
Cell Membrane
GTPase-Activating Proteins
Cytokinesis
Monomeric GTP-Binding Proteins
Endosomes

Cite this

Mai, A., Veltel, S., Pellinen, T., Padzik, A., Coffey, E., Marjomäki, V., & Ivaska, J. (2011). Competitive binding of Rab21 and p120RasGAP to integrins regulates receptor traffic and migration. Journal of Cell Biology, 194(2), 291-306. https://doi.org/10.1083/jcb.201012126
Mai, Anja ; Veltel, Stefan ; Pellinen, Teijo ; Padzik, Artur ; Coffey, Eleanor ; Marjomäki, Varpu ; Ivaska, Johanna. / Competitive binding of Rab21 and p120RasGAP to integrins regulates receptor traffic and migration. In: Journal of Cell Biology. 2011 ; Vol. 194, No. 2. pp. 291-306.
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abstract = "Integrin trafficking from and to the plasma membrane controls many aspects of cell behavior including cell motility, invasion, and cytokinesis. Recruitment of integrin cargo to the endocytic machinery is regulated by the small GTPase Rab21, but the detailed molecular mechanisms underlying integrin cargo recruitment are yet unknown. Here we identify an important role for p120RasGAP (RASA1) in the recycling of endocytosed α/β1-integrin heterodimers to the plasma membrane. Silencing of p120RasGAP attenuated integrin recycling and augmented cell motility. Mechanistically, p120RasGAP interacted with the cytoplasmic domain of integrin α-subunits via its GAP domain and competed with Rab21 for binding to endocytosed integrins. This in turn facilitated exit of the integrin from Rab21- and EEA1-positive endosomes to drive recycling. Our results assign an unexpected role for p120RasGAP in the regulation of integrin traffic in cancer cells and reveal a new concept of competitive binding of Rab GTPases and GAP proteins to receptors as a regulatory mechanism in trafficking.",
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Mai, A, Veltel, S, Pellinen, T, Padzik, A, Coffey, E, Marjomäki, V & Ivaska, J 2011, 'Competitive binding of Rab21 and p120RasGAP to integrins regulates receptor traffic and migration', Journal of Cell Biology, vol. 194, no. 2, pp. 291-306. https://doi.org/10.1083/jcb.201012126

Competitive binding of Rab21 and p120RasGAP to integrins regulates receptor traffic and migration. / Mai, Anja; Veltel, Stefan; Pellinen, Teijo; Padzik, Artur; Coffey, Eleanor; Marjomäki, Varpu; Ivaska, Johanna.

In: Journal of Cell Biology, Vol. 194, No. 2, 2011, p. 291-306.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - Competitive binding of Rab21 and p120RasGAP to integrins regulates receptor traffic and migration

AU - Mai, Anja

AU - Veltel, Stefan

AU - Pellinen, Teijo

AU - Padzik, Artur

AU - Coffey, Eleanor

AU - Marjomäki, Varpu

AU - Ivaska, Johanna

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AB - Integrin trafficking from and to the plasma membrane controls many aspects of cell behavior including cell motility, invasion, and cytokinesis. Recruitment of integrin cargo to the endocytic machinery is regulated by the small GTPase Rab21, but the detailed molecular mechanisms underlying integrin cargo recruitment are yet unknown. Here we identify an important role for p120RasGAP (RASA1) in the recycling of endocytosed α/β1-integrin heterodimers to the plasma membrane. Silencing of p120RasGAP attenuated integrin recycling and augmented cell motility. Mechanistically, p120RasGAP interacted with the cytoplasmic domain of integrin α-subunits via its GAP domain and competed with Rab21 for binding to endocytosed integrins. This in turn facilitated exit of the integrin from Rab21- and EEA1-positive endosomes to drive recycling. Our results assign an unexpected role for p120RasGAP in the regulation of integrin traffic in cancer cells and reveal a new concept of competitive binding of Rab GTPases and GAP proteins to receptors as a regulatory mechanism in trafficking.

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