The Human Minor Histocompatibility Antigen1 Is a RhoGAP

Bart Jan de Kreuk, Antje Schaefer, Eloise C. Anthony, Simon Tol, Mar Fernandez-Borja, Dirk Geerts, Jos Pool, Lothar Hambach, Els Goulmy, Peter L. Hordijk

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The human minor Histocompatibility Antigen HMHA-1 is a major target of immune responses after allogeneic stem cell transplantation applied for the treatment of leukemia and solid tumors. The restriction of its expression to hematopoietic cells and many solid tumors raised questions regarding its cellular functions. Sequence analysis of the HMHA-1 encoding HMHA1 protein revealed the presence of a possible C-terminal RhoGTPase Activating Protein (GAP) domain and an N-terminal BAR domain. Rho-family GTPases, including Rac1, Cdc42, and RhoA are key regulators of the actin cytoskeleton and control cell spreading and migration. RhoGTPase activity is under tight control as aberrant signaling can lead to pathology, including inflammation and cancer. Whereas Guanine nucleotide Exchange Factors (GEFs) mediate the exchange of GDP for GTP resulting in RhoGTPase activation, GAPs catalyze the low intrinsic GTPase activity of active RhoGTPases, resulting in inactivation. Here we identify the HMHA1 protein as a novel RhoGAP. We show that HMHA1 constructs, lacking the N-terminal region, negatively regulate the actin cytoskeleton as well as cell spreading. Furthermore, we show that HMHA1 regulates RhoGTPase activity in vitro and in vivo. Finally, we demonstrate that the HMHA1 N-terminal BAR domain is auto-inhibitory as HMHA1 mutants lacking this region, but not full-length HMHA1, showed GAP activity towards RhoGTPases. In conclusion, this study shows that HMHA1 acts as a RhoGAP to regulate GTPase activity, cytoskeletal remodeling and cell spreading, which are crucial functions in normal hematopoietic and cancer cells.

Original languageEnglish
Article numbere73962
JournalPLoS ONE
Volume8
Issue number9
DOIs
Publication statusPublished - 23 Sep 2013

Cite this

de Kreuk, B. J., Schaefer, A., Anthony, E. C., Tol, S., Fernandez-Borja, M., Geerts, D., ... Hordijk, P. L. (2013). The Human Minor Histocompatibility Antigen1 Is a RhoGAP. PLoS ONE, 8(9), [e73962]. https://doi.org/10.1371/journal.pone.0073962
de Kreuk, Bart Jan ; Schaefer, Antje ; Anthony, Eloise C. ; Tol, Simon ; Fernandez-Borja, Mar ; Geerts, Dirk ; Pool, Jos ; Hambach, Lothar ; Goulmy, Els ; Hordijk, Peter L. / The Human Minor Histocompatibility Antigen1 Is a RhoGAP. In: PLoS ONE. 2013 ; Vol. 8, No. 9.
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abstract = "The human minor Histocompatibility Antigen HMHA-1 is a major target of immune responses after allogeneic stem cell transplantation applied for the treatment of leukemia and solid tumors. The restriction of its expression to hematopoietic cells and many solid tumors raised questions regarding its cellular functions. Sequence analysis of the HMHA-1 encoding HMHA1 protein revealed the presence of a possible C-terminal RhoGTPase Activating Protein (GAP) domain and an N-terminal BAR domain. Rho-family GTPases, including Rac1, Cdc42, and RhoA are key regulators of the actin cytoskeleton and control cell spreading and migration. RhoGTPase activity is under tight control as aberrant signaling can lead to pathology, including inflammation and cancer. Whereas Guanine nucleotide Exchange Factors (GEFs) mediate the exchange of GDP for GTP resulting in RhoGTPase activation, GAPs catalyze the low intrinsic GTPase activity of active RhoGTPases, resulting in inactivation. Here we identify the HMHA1 protein as a novel RhoGAP. We show that HMHA1 constructs, lacking the N-terminal region, negatively regulate the actin cytoskeleton as well as cell spreading. Furthermore, we show that HMHA1 regulates RhoGTPase activity in vitro and in vivo. Finally, we demonstrate that the HMHA1 N-terminal BAR domain is auto-inhibitory as HMHA1 mutants lacking this region, but not full-length HMHA1, showed GAP activity towards RhoGTPases. In conclusion, this study shows that HMHA1 acts as a RhoGAP to regulate GTPase activity, cytoskeletal remodeling and cell spreading, which are crucial functions in normal hematopoietic and cancer cells.",
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de Kreuk, BJ, Schaefer, A, Anthony, EC, Tol, S, Fernandez-Borja, M, Geerts, D, Pool, J, Hambach, L, Goulmy, E & Hordijk, PL 2013, 'The Human Minor Histocompatibility Antigen1 Is a RhoGAP' PLoS ONE, vol. 8, no. 9, e73962. https://doi.org/10.1371/journal.pone.0073962

The Human Minor Histocompatibility Antigen1 Is a RhoGAP. / de Kreuk, Bart Jan; Schaefer, Antje; Anthony, Eloise C.; Tol, Simon; Fernandez-Borja, Mar; Geerts, Dirk; Pool, Jos; Hambach, Lothar; Goulmy, Els; Hordijk, Peter L.

In: PLoS ONE, Vol. 8, No. 9, e73962, 23.09.2013.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - de Kreuk, Bart Jan

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AU - Tol, Simon

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AU - Geerts, Dirk

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AU - Hordijk, Peter L.

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de Kreuk BJ, Schaefer A, Anthony EC, Tol S, Fernandez-Borja M, Geerts D et al. The Human Minor Histocompatibility Antigen1 Is a RhoGAP. PLoS ONE. 2013 Sep 23;8(9). e73962. https://doi.org/10.1371/journal.pone.0073962