GPR78 promotes lung cancer cell migration and metastasis by activation of Gαq-Rho GTPase pathway

  • Dong, Dan-Dan (Department of Pathology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital) ;
  • Zhou, Hui (Department of Thoracic Medicine, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University) ;
  • Li, Gao (Thoracic Surgery, Hainan General Hospital)
  • Received : 2016.08.04
  • Accepted : 2016.09.23
  • Published : 2016.11.30


GPR78 is an orphan G-protein coupled receptor (GPCR) that is predominantly expressed in human brain tissues. Currently, the function of GPR78 is unknown. This study revealed that GPR78 was expressed in lung cancer cells and functioned as a novel regulator of lung cancer cell migration and metastasis. We found that knockdown of GPR78 in lung cancer cells suppressed cell migration. Moreover, GPR78 modulated the formation of actin stress fibers in A549 cells, in a RhoA- and Rac1-dependent manner. At the molecular level, GPR78 regulated cell motility through the activation of $G{\alpha}q$-RhoA/Rac1 pathway. We further demonstrated that in vivo, the knockdown of GPR78 inhibited lung cancer cell metastasis. These findings suggest that GPR78 is a novel regulator for lung cancer metastasis and may serve as a potential drug target against metastatic human lung cancer.


GPR78;Lung cancer;Metastasis;Rho GTPase


  1. Kroeze WK, Sheffler DJ and Roth BL (2003) G-protein-coupled receptors at a glance. J Cell Sci 116, 4867-4869
  2. Hermans E (2003) Biochemical and pharmacological control of the multiplicity of coupling at G-protein-coupled receptors. Pharmacol Ther 99, 25-44
  3. Wong SK (2003) G protein selectivity is regulated by multiple intracellular regions of GPCRs. Neurosignals 12, 1-12
  4. Tang XL, Wang Y, Li DL, Luo J and Liu MY (2012) Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets. Acta Pharmacol Sin 33, 363-371
  5. Lee DK, Nguyen T, Lynch KR et al (2001) Discovery and mapping of ten novel G protein-coupled receptor genes. Gene 275, 83-91
  6. Jones PG, Nawoschik SP, Sreekumar K et al (2007) Tissue distribution and functional analyses of the constitutively active orphan G protein coupled receptors, GPR26 and GPR78. Biochim Biophys Acta 1770, 890-901
  7. Hall A (2012) Rho family GTPases. Biochem Soc Trans 40, 1378-1382
  8. Fukata M, Nakagawa M and Kaibuchi K (2003) Roles of Rho-family GTPases in cell polarisation and directional migration. Curr Opin Cell Biol 15, 590-597
  9. Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279, 509-514
  10. Lutz S, Shankaranarayanan A, Coco C et al (2007) Structure of Galphaq-p63RhoGEF-RhoA complex reveals a pathway for the activation of RhoA by GPCRs. Science 318, 1923-1927
  11. Momotani K, Artamonov MV, Utepbergenov D, Derewenda U, Derewenda ZS and Somlyo AV (2011) p63RhoGEF couples Galpha(q/11)-mediated signaling to Ca2+ sensitization of vascular smooth muscle contractility. Circ Res 109, 993-1002
  12. Yamaguchi H and Condeelis J (2007) Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta 1773, 642-652
  13. Tojkander S, Gateva G and Lappalainen P (2012) Actin stress fibers--assembly, dynamics and biological roles. J Cell Sci 125, 1855-1864
  14. Iguchi T, Sakata K, Yoshizaki K, Tago K, Mizuno N and Itoh H (2008) Orphan G protein-coupled receptor GPR56 regulates neural progenitor cell migration via a G alpha 12/13 and Rho pathway. J Biol Chem 283, 14469-14478
  15. Cotton M and Claing A (2009) G protein-coupled receptors stimulation and the control of cell migration. Cell Signal 21, 1045-1053
  16. Ward Y, Lake R, Martin PL et al (2013) CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model. Oncogene 32, 2726-2738
  17. Yuan B, Cui J, Wang W and Deng K (2016) Galpha12/13 signaling promotes cervical cancer invasion through the RhoA/ROCK-JNK signaling axis. Biochem Biophys Res Commun 473, 1240-1246
  18. Schumacher SM, Gao E, Cohen M, Lieu M, Kurt Chuprun J and Koch WJ (2016) A peptide of the RGS domain of GRK2 binds and inhibits Galphaq to suppress pathological cardiac hypertrophy and dysfunction. Sci Signal 9, ra30
  19. Underwood SL, Christoforou A, Thomson PA et al (2006) Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia. Mol Psychiatry 11, 384-394
  20. Gulhati P, Bowen KA, Liu J et al (2011) mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res 71, 3246-3256
  21. Zhao P, Zhang W, Wang SJ et al (2011) HAb18G/CD147 promotes cell motility by regulating annexin II-activated RhoA and Rac1 signaling pathways in hepatocellular carcinoma cells. Hepatology 54, 2012-2024
  22. Shashidhar S, Lorente G, Nagavarapu U et al (2005) GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion. Oncogene 24, 1673-1682
  23. Huang Y, Fan J, Yang J and Zhu GZ (2008) Characterization of GPR56 protein and its suppressed expression in human pancreatic cancer cells. Mol Cell Biochem 308, 133-139
  24. Tang X, Jin R, Qu G et al (2013) GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Galphaq-p63RhoGEF-Rho GTPase pathway. Cancer Res 73, 6206-6218
  25. Johansson BB, Minsaas L and Aragay AM (2005) Proteasome involvement in the degradation of the G(q) family of Galpha subunits. FEBS J 272, 5365-5377

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