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CB1 Cannabinoid Receptors Stimulate Gβγ-GRK2-Mediated FAK Phosphorylation at Tyrosine 925 to Regulate ERK Activation Involving Neuronal Focal Adhesions.
Front Cell Neurosci. 2020; 14:176.FC

Abstract

CB1 cannabinoid receptors (CB1) are abundantly expressed in the nervous system where they regulate focal adhesion kinase (FAK) and the mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase 1 and 2 (ERK1/2). However, the role of CB1-stimulated FAK 925 tyrosine phosphorylation (Tyr-P) in regulating ERK1/2 activation remains undefined. Here, immunoblotting analyses using antibodies against FAK phospho-Tyr 925 and ERK2 phospho-Tyr 204 demonstrated CB1-stimulated FAK 925 Tyr-P and ERK2 204 Tyr-P (0-5 min) which was followed by a decline in Tyr-P (5-20 min). CB1 stimulated FAK-Grb2 association and Ras-mediated ERK2 activation. The FAK inhibitors Y11 and PF 573228 abolished FAK 925 Tyr-P and partially inhibited ERK2 204 Tyr-P. FAK 925 Tyr-P and ERK2 204 Tyr-P were adhesion-dependent, required an intact actin cytoskeleton, and were mediated by integrins, Flk-1 vascular endothelial growth factor receptors, and epidermal growth factor receptors. FAK 925 Tyr-P and ERK2 204 Tyr-P were blocked by the Gβγ inhibitor gallein, a GRK2 inhibitor, and GRK2 siRNA silencing, suggesting Gβγ and GRK2 participate in FAK-mediated ERK2 activation. Together, these studies indicate FAK 925 Tyr-P occurs concurrently with CB1-stimulated ERK2 activation and requires the actin cytoskeleton and Gi/oβγ-GRK2-mediated cross-talk between CB1, integrins, and receptor tyrosine kinases (RTKs).

Authors+Show Affiliations

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, United States.Department of Biological and Biomedical Sciences, Julius L. Chambers Biomedical and Biotechnology Research Institute, North Carolina Central University, Durham, NC, United States.Department of Biological and Biomedical Sciences, Julius L. Chambers Biomedical and Biotechnology Research Institute, North Carolina Central University, Durham, NC, United States.Department of Biological and Biomedical Sciences, Julius L. Chambers Biomedical and Biotechnology Research Institute, North Carolina Central University, Durham, NC, United States.Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32655375

Citation

Dalton, George D., et al. "CB1 Cannabinoid Receptors Stimulate Gβγ-GRK2-Mediated FAK Phosphorylation at Tyrosine 925 to Regulate ERK Activation Involving Neuronal Focal Adhesions." Frontiers in Cellular Neuroscience, vol. 14, 2020, p. 176.
Dalton GD, Carney ST, Marshburn JD, et al. CB1 Cannabinoid Receptors Stimulate Gβγ-GRK2-Mediated FAK Phosphorylation at Tyrosine 925 to Regulate ERK Activation Involving Neuronal Focal Adhesions. Front Cell Neurosci. 2020;14:176.
Dalton, G. D., Carney, S. T., Marshburn, J. D., Norford, D. C., & Howlett, A. C. (2020). CB1 Cannabinoid Receptors Stimulate Gβγ-GRK2-Mediated FAK Phosphorylation at Tyrosine 925 to Regulate ERK Activation Involving Neuronal Focal Adhesions. Frontiers in Cellular Neuroscience, 14, 176. https://doi.org/10.3389/fncel.2020.00176
Dalton GD, et al. CB1 Cannabinoid Receptors Stimulate Gβγ-GRK2-Mediated FAK Phosphorylation at Tyrosine 925 to Regulate ERK Activation Involving Neuronal Focal Adhesions. Front Cell Neurosci. 2020;14:176. PubMed PMID: 32655375.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CB1 Cannabinoid Receptors Stimulate Gβγ-GRK2-Mediated FAK Phosphorylation at Tyrosine 925 to Regulate ERK Activation Involving Neuronal Focal Adhesions. AU - Dalton,George D, AU - Carney,Skyla T, AU - Marshburn,Jamie D, AU - Norford,Derek C, AU - Howlett,Allyn C, Y1 - 2020/06/23/ PY - 2020/03/31/received PY - 2020/05/22/accepted PY - 2020/7/14/entrez PY - 2020/7/14/pubmed PY - 2020/7/14/medline KW - CB1 KW - ERK KW - FAK KW - GRK2 KW - Grb2 KW - Gβγ SP - 176 EP - 176 JF - Frontiers in cellular neuroscience JO - Front Cell Neurosci VL - 14 N2 - CB1 cannabinoid receptors (CB1) are abundantly expressed in the nervous system where they regulate focal adhesion kinase (FAK) and the mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase 1 and 2 (ERK1/2). However, the role of CB1-stimulated FAK 925 tyrosine phosphorylation (Tyr-P) in regulating ERK1/2 activation remains undefined. Here, immunoblotting analyses using antibodies against FAK phospho-Tyr 925 and ERK2 phospho-Tyr 204 demonstrated CB1-stimulated FAK 925 Tyr-P and ERK2 204 Tyr-P (0-5 min) which was followed by a decline in Tyr-P (5-20 min). CB1 stimulated FAK-Grb2 association and Ras-mediated ERK2 activation. The FAK inhibitors Y11 and PF 573228 abolished FAK 925 Tyr-P and partially inhibited ERK2 204 Tyr-P. FAK 925 Tyr-P and ERK2 204 Tyr-P were adhesion-dependent, required an intact actin cytoskeleton, and were mediated by integrins, Flk-1 vascular endothelial growth factor receptors, and epidermal growth factor receptors. FAK 925 Tyr-P and ERK2 204 Tyr-P were blocked by the Gβγ inhibitor gallein, a GRK2 inhibitor, and GRK2 siRNA silencing, suggesting Gβγ and GRK2 participate in FAK-mediated ERK2 activation. Together, these studies indicate FAK 925 Tyr-P occurs concurrently with CB1-stimulated ERK2 activation and requires the actin cytoskeleton and Gi/oβγ-GRK2-mediated cross-talk between CB1, integrins, and receptor tyrosine kinases (RTKs). SN - 1662-5102 UR - https://www.unboundmedicine.com/medline/citation/32655375/CB1_Cannabinoid_Receptors_Stimulate_Gβγ-GRK2-Mediated_FAK_Phosphorylation_at_Tyrosine_925_to_Regulate_ERK_Activation_Involving_Neuronal_Focal_Adhesions L2 - https://doi.org/10.3389/fncel.2020.00176 DB - PRIME DP - Unbound Medicine ER -
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