RhoH plays distinct roles in T-cell migrations induced by different doses of SDF1 alpha.
Hematopoietic-specific RhoGTPase RhoH displays an important role in regulating T-cell development, a process that is accompanied by ordered and directed migration of progenitors through thymus. While RhoGTPases are key regulators of cytokinesis, the precise role of RhoH in T-cell migration is unknown. Here, by using Jurkat cell migration as a model, we found that RhoH is required for cell migration in response to the high concentration of SDF1 alpha but displays inhibitory roles in regulating migration in the absence of SDF1 alpha or in the range of low concentrations. We further found that RhoH-mediated migration requires PAK1 but not ITK. Indeed, both the low and high concentrations of SDF1 alpha activate PAK1 but only the high concentration-induced activation of PAK1 requires RhoH. Further study of the RhoH-PAK interaction revealed that RhoH is able to bind and activate PAK1, indicating that RhoH plays a positive role in response to the high concentration of SDF1 alpha. In contrast, at rest, RhoH indirectly inhibits Slp76/ITK activity through its modulation on TCR signaling, supporting a negative regulatory role for RhoH when SDF1 alpha is insufficient to activate the RhoH-PAK1 pathway. Together, our study uncovered a dual role for RhoH in SDF1 alpha signaling in T-cell responses.
Wang
Hong
H
Division of Hematology and Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave., Boston, MA 02215, USA. howang@rci.rutgers.edu
Zeng
Xin
X
Fan
Zhigang
Z
Lim
Bing
B
D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D014157:Transcription Factors / Q000502:physiology*; D054462:p21-Activated Kinases / Q000378:metabolism / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000502:physiology*
D054377:Chemokine CXCL12; C447841:RhoH protein, human; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D020741:rho GTP-Binding Proteins