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. Apr-Jun 2012;3(2):97-101.
doi: 10.4161/sgtp.19138.

RRas2, RhoG and T-cell Phagocytosis

Free PMC article

RRas2, RhoG and T-cell Phagocytosis

Balbino Alarcón et al. Small GTPases. .
Free PMC article


Activating mutations and overexpression of classical Ras subfamily members (K-Ras, N-Ras and H-Ras) have been widely investigated as key events in the development of human cancers. The role in cancer of its closest relatives, the Ras-related (RRas) subfamily members, has been less studied despite the fact that one of its members (TC21 or RRas2) is strongly transforming in vitro. Nevertheless, and in spite the paucity of publications, several studies have shown that wild type TC21 is overexpressed in different types of carcinomas and lymphomas. If the study of RRas members in cancer is still in its infancy, their role in physiological functions is even behind. For instance, T and B cell immunologists still use the vague term "Ras activation" without indication of what Ras family molecule is indeed intervening. In this view, we discuss the participation of TC21 in the specific process of T cell antigen receptor internalization from the immunological synapse and acquisition of membrane fragments from the antigen presenting cells by phagocytosis.


Figure 1. Sequence comparison of classical and Ras-related subfamily members. The amino acid sequence of the three classical human (h) Ras proteins is compared with these of the three R-Ras subfamily and with the two Ras subfamily members of Drosophila melanogaster (d). RRas is RRas1, TC21 is RRas2 and MRas is RRas3. The amino acid residues shared by at least two classical Ras members are in red. The positions in TC21 that differ from classical Ras are in bold blue type. The positions not conserved in classical Ras or TC21 are in purple. The sequences corresponding to the effector loops switch I and switch II and the G1, G4 and G5 loops are underlined in green. Drosophila’s Ras1 resembles the classical Ras, whereas Drosophila’s Ras2 resembles TC21.
Figure 2. Hypothetical integration of TC21 and RhoG into a common phagocytotic pathway triggered by the TCR. TCR engagement of pMHC leads to the formation of an IS where the TCR and pMHC coalesce at the center of the structure (cSMAC). The activation of TC21 by the TCR leads to the direct recruitment of the p110δ subunit of PI3K, which is activated and phosphorylates phosphatidyl inositol (4,5) bisphosphate (PIP2) to phosphatidyl inositol (3,4,5) trisphosphate (PIP3). The direct recruitment of TC21 by the TCR followed by the direct recruitment of p110δ by TC21 increases the PIP3 concentration proximal to the site of TCR engagement. PIP3 recruits to the plasma membrane and activates the PH domain-containing protein TRIO, a GEF for RhoG, which is activated accordingly. RhoG forms a trimolecular complex with ELMO and DOCK180. The latter is a GEF for Rac1, which is activated and promotes the polymerization of the actin cytoskeleton necessary to trigger phagocytosis (trogocytosis) of a fragment of the APC membrane, together with the internalization of the TCR accumulated at the cSMAC.

Comment on

  • Iborra S, Soto M, Stark-Aroeira L, Castellano E, Alarcón B, Alonso C, et al. H-ras and N-ras are dispensable for T-cell development and activation but critical for protective Th1 immunity. Blood. 2011;117:5102–11. doi: 10.1182/blood-2010-10-315770.

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