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Cited by 81Protein Kinase Regulation and GTPase SignalingChemokine receptors and signalingHematopoietic Stem Cell Transplantation

Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells

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Chae, Hee-Don, Lee, Katherine E., Williams, David A., Gu, Yi·2008·Blood
DOI 10.1182/blood-2007-06-093237PMC PMC2254535
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Abstract

RhoH, a hematopoietic-specific and constitutively active member of the Rho guanosine triphosphatase (GTPase) family, has been implicated in the negative regulation of Rac GTPase-mediated signaling in hematopoietic cells. However, the molecular mechanisms underlying the functional interaction between RhoH and Rac in primary cells are poorly understood. Here we show that deletion of Rhoh in hematopoietic progenitor cells (HPCs) leads to increased stromal-derived factor-1α (SDF-1α)–induced chemotaxis and chemokinesis (random migration). The abnormally enhanced migration of Rhoh−/− HPCs is associated with increased Rac1 activity and translocation of Rac1 protein to the cell membrane, where it colocalizes with cortical filamentous-actin (F-actin) and lipid rafts. Expression of the dominant-negative mutant Rac1N17 inhibits the cortical F-actin assembly and chemotaxis of wild-type and Rhoh−/− HPCs to the same extent. Conversely, overexpression of RhoH in HPCs blocks the membrane translocation of Rac1–enhanced green fluorescence protein (EGFP) and active Rac1V12–EGFP proteins and impairs cortical F-actin assembly and chemotaxis in response to SDF-1α stimulation. Furthermore, we demonstrate that the subcellular localization and inhibitory function of RhoH in HPCs are regulated by C-terminal motifs, including a CKIF prenylation site. Together, we have identified an antagonistic role of RhoH in regulation of cortical F-actin assembly and chemotaxis via suppressing Rac1 membrane targeting and activation in primary HPCs.

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Crossref · 10.1182/blood-2007-06-093237

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  • In myeloid 32D cells transduced with RhoH, RhoH localises at the membrane, whereas deletion of the CaaX box leads to exclusively cytoplasmic localisation.

    “In myeloid 32D cells transduced with RhoH, RhoH was localised at the membrane while deletion of the CaaX box led to an exclusively cytoplasmic localisation.”

    From The small GTPase RhoH is an atypical regulator of haematopoietic cells (2008) · cites this paper as [20]

    The Results (Figure 6B,C; page not provided) show that most RhoH in 32D myeloid progenitor cells was in membrane-containing fractions and that deleting its CKIF prenylation site abolished membrane localization. They do not support “exclusively cytoplasmic”: the C-terminally truncated mutant was also detected in the nuclear fraction (36% for RhoHdCT). (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • RhoH activity is modulated by interaction with other Rho GTPases, transcriptional regulation, or phosphorylation rather than through classical GTPase cycling and effector modulation.

    “Its activity is modulated by interaction with other Rho GTPases [19,20], transcriptional regulation [19] or phosphorylation [21] rather than through the classical cycling process and modulation by effector proteins.”

    From The small GTPase RhoH is an atypical regulator of haematopoietic cells (2008) · cites this paper as [20]

  • RhoH regulates the cytoskeleton in haematopoietic cells as an antagonist of Rac1.

    “However, more recent studies using bone marrow from RhoH-deficient mice or haematopoietic cells transduced with RhoH showed that RhoH does have an effect in regulation of the cytoskeleton in haematopoietic cells, if only as an antagonist of another Rho GTPase, Rac1 [20,27].”

    From The small GTPase RhoH is an atypical regulator of haematopoietic cells (2008) · cites this paper as [20]

  • Only the membrane-localised form of RhoH is able to downregulate Rac1 efficiently.

    “Since active GTP-bound Rac is localised at the membrane through interaction of its CaaX box with lipid rafts, only the membrane-localised form of RhoH is able to downregulate Rac1 efficiently [20].”

    From The small GTPase RhoH is an atypical regulator of haematopoietic cells (2008) · cites this paper as [20]

  • The C-terminal prenylation motif of the CaaX box is an important regulator of the inhibitory effect of RhoH on Rac.

    “The authors were able to show that the C-terminal prenylation motif of the CaaX box is an important regulator of the inhibitory effect of RhoH on Rac.”

    From The small GTPase RhoH is an atypical regulator of haematopoietic cells (2008) · cites this paper as [20]

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Cited by

Sorted by citations

Authors
Chae, H.-D., Lee, K. E., Williams, D. A., & Gu, Y.
Affiliations
Cincinnati Children's Hospital Medical Center (US)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2008-03-01
Volume
111
Issue
5
Pages
2597-2605
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2007-06-093237
PMC
PMC2254535
OpenAlex
W2159683137
Cited by
81
References
1
Citations by year
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FWCI
2.51
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (CA 113969, R01CA113969)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK062757, DK 62757)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
Keywords
RhoH, Rac1, Rho GTPases, hematopoietic progenitor cells, chemotaxis, chemokinesis, stromal-derived factor-1α, actin cytoskeleton, lipid rafts, dominant negative Rac1
MeSH terms
Actins, Amino Acid Sequence, Animals, Cell Membrane, Chemotaxis, Cytoskeleton, Hematopoietic Stem Cells, Mice, Inbred C57BL, Molecular Sequence Data, Subcellular Fractions, Transcription Factors, Protein Prenylation, rho GTP-Binding Proteins, Amino Acid Motifs, rac1 GTP-Binding Protein, Protein Transport, Mice

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