What is Rho-dependent IL-2 receptor endocytosis?
Internalization of transmembrane receptors was thought to occur exclusively via clathrin-mediated endocytosis (CME). However, the discovery of clathrin-independent endocytic routes, in particular, the pathway that mediates the internalization of the cytokine receptor interleukin-2 (IL-2R), raises into question the interchangeable use of the term ‘receptor-mediated endocytosis’ as a synonym for CME [1]. It has been proposed that the specific endocytic mechanism is used to describe the pathway.
A clathrin-independent pathway dependent on RhoA and regulated by PI3K
The endocytosis of the cytokine receptor IL-2R, occurs via a constitutive, clathrin and caveolae-independent, dynamin-dependent route. This pathway is dependent on the Rho small GTPase RhoA [2] and is regulated by the lipid kinase, phosphoinositide 3-kinase (PI3K) [3]. The current model for IL2-R endocytosis is as follows: 1) IL-2R activates PI3K by interacting with its regulatory p85 subunit, leading to the production of PIP3 at the membrane 2) PIP3 induces Vav2, a guanine nucleotide exchange factor (GEF) for Rac1, that activates Rac1 3) Rac1-GTP directly binds to p85 and thus is recruited to sites containing IL2-R 4) This activates the downstream target of Rac1, the p21-activated kinase1 (Pak1), which phosphorylates cortactin, promoting its association with neuronal Wiskott-Aldrich syndrome proteins (N-WASP), activating actin polymerization. [4] [5] [3] [6].
References
- Doherty GJ, and McMahon HT. Mechanisms of endocytosis. Annu. Rev. Biochem. 2009; 78:857-902. [PMID: 19317650]
- Lamaze C, Dujeancourt A, Baba T, Lo CG, Benmerah A, and Dautry-Varsat A. Interleukin 2 receptors and detergent-resistant membrane domains define a clathrin-independent endocytic pathway. Mol. Cell 2001; 7(3):661-71. [PMID: 11463390]
- Basquin C, Malardé V, Mellor P, Anderson DH, Meas-Yedid V, Olivo-Marin J, Dautry-Varsat A, and Sauvonnet N. The signalling factor PI3K is a specific regulator of the clathrin-independent dynamin-dependent endocytosis of IL-2 receptors. J. Cell. Sci. 2013; 126(Pt 5):1099-108. [PMID: 23345407]
- Grassart A, Dujeancourt A, Lazarow PB, Dautry-Varsat A, and Sauvonnet N. Clathrin-independent endocytosis used by the IL-2 receptor is regulated by Rac1, Pak1 and Pak2. EMBO Rep. 2008; 9(4):356-62. [PMID: 18344974]
- Grassart A, Meas-Yedid V, Dufour A, Olivo-Marin J, Dautry-Varsat A, and Sauvonnet N. Pak1 phosphorylation enhances cortactin-N-WASP interaction in clathrin-caveolin-independent endocytosis. Traffic 2010; 11(8):1079-91. [PMID: 20444238]
- Basquin C, and Sauvonnet N. Phosphoinositide 3-kinase at the crossroad between endocytosis and signaling of cytokine receptors. Commun Integr Biol 2013; 6(4):e24243. [PMID: 23986799]
