RAC1

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Protein-coding gene in humans

title: "RAC1" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public description: "Protein-coding gene in humans" topic_path: "uncategorized" source: "https://en.wikipedia.org/wiki/RAC1" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Protein-coding gene in humans ::

Ras-related C3 botulinum toxin substrate 1, is a protein that in humans is encoded by the RAC1 gene. This gene can produce a variety of alternatively spliced versions of the Rac1 protein, which appear to carry out different functions.

Function

Rac1 is a small (~21 kDa) signalling G protein (more specifically a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of GLUT4 translocation to glucose uptake, cell growth, cytoskeletal reorganization, antimicrobial cytotoxicity, and the activation of protein kinases.

Rac1 is a pleiotropic regulator of many cellular processes, including the cell cycle, cell-cell adhesion, motility (through the actin network), and of epithelial differentiation (proposed to be necessary for maintaining epidermal stem cells).

Role in glucose transport

Rac1 is expressed in significant amounts in insulin sensitive tissues, such as adipose tissue and skeletal muscle. Here Rac1 regulated the translocation of glucose transporting GLUT4 vesicles from intracellular compartments to the plasma membrane. In response to insulin, this allows for blood glucose to enter the cell to lower blood glucose. In conditions of obesity and type 2 diabetes, Rac1 signalling in skeletal muscle is dysfunctional, suggesting that Rac1 contributes to the progression of the disease. Rac1 protein is also necessary for glucose uptake in skeletal muscle activated by exercise and muscle stretching.

Clinical significance

Cancer

Along with other subfamily of Rac and Rho proteins, they exert an important regulatory role specifically in cell motility and cell growth. Rac1 has ubiquitous tissue expression, and drives cell motility by formation of lamellipodia. In order for cancer cells to grow and invade local and distant tissues, deregulation of cell motility is one of the hallmark events in cancer cell invasion and metastasis. Overexpression of a constitutively active Rac1 V12 in mice caused a tumour that is phenotypically indistinguishable from human Kaposi's sarcoma. Activating or gain-of-function mutations of Rac1 are shown to play active roles in promoting mesenchymal-type of cell movement assisted by NEDD9 and DOCK3 protein complex. Such abnormal cell motility may result in epithelial mesenchymal transition (EMT) – a driving mechanism for tumour metastasis as well as drug-resistant tumour relapse.

Activating mutations in Rac1 have been recently discovered in large-scale genomic studies involving melanoma and non-small cell lung cancer. As a result, Rac1 is considered a therapeutic target for many of these diseases.

Other diseases

Dominant negative or constitutively active germline RAC1 mutations cause diverse phenotypes that have been grouped together as Mental Retardation Type 48. Most mutations cause microcephaly while some specific changes appear to result in macrocephaly.

As a drug target

A few recent studies have also exploited targeted therapy to suppress tumour growth by pharmacological inhibition of Rac1 activity in metastatic melanoma and liver cancer as well as in human breast cancer. For example, Rac1-dependent pathway inhibition resulted in the reversal of tumour cell phenotypes, suggesting Rac1 as a predictive marker and therapeutic target for trastuzumab-resistant breast cancer. However, given Rac1's role in glucose transport, drugs that inhibit Rac1 could potentially be harmful to glucose homeostasis.

Interactions

RAC1 has been shown to interact with:

References

References

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  2. (November 1999). "Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors". Oncogene.
  3. (February 2013). "The Rac1 splice form Rac1b promotes K-ras-induced lung tumorigenesis". Oncogene.
  4. (September 2016). "Rac1 governs exercise-stimulated glucose uptake in skeletal muscle through regulation of GLUT4 translocation in mice". The Journal of Physiology.
  5. (March 2016). "Ras-related C3 Botulinum Toxin Substrate (Rac) and Src Family Kinases (SFK) Are Proximal and Essential for Phosphatidylinositol 3-Kinase (PI3K) Activation in Natural Killer (NK) Cell-mediated Direct Cytotoxicity against Cryptococcus neoformans". The Journal of Biological Chemistry.
  6. (October 2006). "Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking". Trends in Cell Biology.
  7. (July 2010). "Crucial role of the small GTPase Rac1 in insulin-stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemma". FASEB Journal.
  8. (February 2014). "Akt and Rac1 signaling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance". Cellular Signalling.
  9. (June 2013). "Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle". Diabetes.
  10. (April 2013). "Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle". Diabetes.
  11. (February 2015). "Stretch-stimulated glucose transport in skeletal muscle is regulated by Rac1". The Journal of Physiology.
  12. (September 2010). "Rac and Rho GTPases in cancer cell motility control". Cell Communication and Signaling.
  13. (March 2011). "Hallmarks of cancer: the next generation". Cell.
  14. (May 2009). "Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma". Proceedings of the National Academy of Sciences of the United States of America.
  15. (October 2008). "Rac activation and inactivation control plasticity of tumor cell movement". Cell.
  16. (July 2012). "Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression". Science Translational Medicine.
  17. (March 2012). "RAC1 activation mediates Twist1-induced cancer cell migration". Nature Cell Biology.
  18. (July 2012). "A landscape of driver mutations in melanoma". Cell.
  19. (September 2012). "Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma". Nature Genetics.
  20. (November 2007). "Rac1 activity regulates proliferation of aggressive metastatic melanoma". Experimental Cell Research.
  21. (July 2012). "Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression". Science Translational Medicine.
  22. (July 2012). "Got a light? Illuminating lung cancer". Science Translational Medicine.
  23. (September 2017). "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes". American Journal of Human Genetics.
  24. (November 2011). "Silencing of Rac1 modifies lung cancer cell migration, invasion and actin cytoskeleton rearrangements and enhances chemosensitivity to antitumor drugs". International Journal of Molecular Medicine.
  25. (June 2009). "Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer". Molecular Cancer Therapeutics.
  26. (June 2008). "Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway". Hepatology.
  27. (August 2001). "Differential binding of arfaptin 2/POR1 to ADP-ribosylation factors and Rac1". Biochemical and Biophysical Research Communications.
  28. (August 1996). "Identification of a novel Rac1-interacting protein involved in membrane ruffling". The EMBO Journal.
  29. (May 2001). "The structural basis of Arfaptin-mediated cross-talk between Rac and Arf signalling pathways". Nature.
  30. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology.
  31. (August 2001). "Crystal structure of the Rac1-RhoGDI complex involved in nadph oxidase activation". Biochemistry.
  32. (January 2000). "Mapping the binding site for the GTP-binding protein Rac-1 on its inhibitor RhoGDI-1". Structure.
  33. (January 1998). "Differential properties of D4/LyGDI versus RhoGDI: phosphorylation and rho GTPase selectivity". FEBS Letters.
  34. (August 2001). "Mechanism of NADPH oxidase activation by the Rac/Rho-GDI complex". Biochemistry.
  35. (May 2001). "Interactions between Rho GTPases and Rho GDP dissociation inhibitor (Rho-GDI)". Biochimie.
  36. (December 2000). "IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling". Nature.
  37. (December 2001). "The formin/diaphanous-related protein, FHOS, interacts with Rac1 and activates transcription from the serum response element". The Journal of Biological Chemistry.
  38. (September 2000). "FRL, a novel formin-related protein, binds to Rac and regulates cell motility and survival of macrophages". Molecular and Cellular Biology.
  39. (September 1996). "Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1". The Journal of Biological Chemistry.
  40. (June 2002). "Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170". Cell.
  41. (June 1996). "IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs". The EMBO Journal.
  42. (September 1996). "The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases". Molecular and Cellular Biology.
  43. (July 2001). "Transactivation by the p65 subunit of NF-kappaB in response to interleukin-1 (IL-1) involves MyD88, IL-1 receptor-associated kinase 1, TRAF-6, and Rac1". Molecular and Cellular Biology.
  44. (June 2000). "Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase". FEBS Letters.
  45. (March 1997). "Interaction of Nck-associated protein 1 with activated GTP-binding protein Rac". The Biochemical Journal.
  46. (April 1998). "Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA". The Journal of Biological Chemistry.
  47. (July 2003). "RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo". Nature.
  48. (March 2003). "ArhGAP15, a novel human RacGAP protein with GTPase binding property". FEBS Letters.
  49. (June 2000). "A human homolog of the C. elegans polarity determinant Par-6 links Rac and Cdc42 to PKCzeta signaling and cell transformation". Current Biology.
  50. (February 2001). "Human homologues of the Caenorhabditis elegans cell polarity protein PAR6 as an adaptor that links the small GTPases Rac and Cdc42 to atypical protein kinase C". Genes to Cells.
  51. (September 2003). "GC-GAP, a Rho family GTPase-activating protein that interacts with signaling adapters Gab1 and Gab2". The Journal of Biological Chemistry.
  52. (February 2003). "Characterization of a brain-specific Rho GTPase-activating protein, p200RhoGAP". The Journal of Biological Chemistry.
  53. (October 2000). "Regulation of STAT3 by direct binding to the Rac1 GTPase". Science.
  54. (December 2000). "Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1". Nature.
  55. (December 2001). "Trp(56) of rac1 specifies interaction with a subset of guanine nucleotide exchange factors". The Journal of Biological Chemistry.

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