Porphyromonas gingivalis-Stimulated TACE Activation for TGF-α Ectodomain Shedding and EGFR Transactivation in Salivary Gland Cells Requires Rac1-Dependent p38 MAPK Membrane Localization
Affiliation(s)
Research Center, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, Newark, USA.
Research Center, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, Newark, USA.
ABSTRACT
Oral mucosal inflammatory responses to P. gingivalis and its key virulence factor, lipopolysaccharide (LPS), are characterized by a massive rise in proinflammatory cytokine production, up-regu- lation in mitogen-activated protein kinase (MAPK) cascade, and the induction in epidermal growth factor receptor (EGFR) activation. In this study, we report that stimulation of salivary gland acinar cells with P. gingivalis LPS leads to p38 MAPK-dependent release of soluble TGF-α ligand and the increase in EGFR phosphorylation. Further, we show that the LPS-induced TGF-α shedding and EGFR transactivation involve the activation of membrane-associated metalloprotease, TACE also known as ADAM17, through phosphorylation by p38 MAPK, and require Rac1 participation. Moreover, we demonstrate that blocking the Rac1 activation leads to the suppression in the membrane translocation of Rac1 as well as p38, thus indicating that the LPS-elicited p38 membrane recruitment for TACE phosphorylation requires colocalization with Rac1. Hence, our findings imply that Rac1 membrane translocation serves as an essential platform for the localization of p38 with TACE, TGF-α ectodomain shedding, and the EGFR activation.
Oral mucosal inflammatory responses to P. gingivalis and its key virulence factor, lipopolysaccharide (LPS), are characterized by a massive rise in proinflammatory cytokine production, up-regu- lation in mitogen-activated protein kinase (MAPK) cascade, and the induction in epidermal growth factor receptor (EGFR) activation. In this study, we report that stimulation of salivary gland acinar cells with P. gingivalis LPS leads to p38 MAPK-dependent release of soluble TGF-α ligand and the increase in EGFR phosphorylation. Further, we show that the LPS-induced TGF-α shedding and EGFR transactivation involve the activation of membrane-associated metalloprotease, TACE also known as ADAM17, through phosphorylation by p38 MAPK, and require Rac1 participation. Moreover, we demonstrate that blocking the Rac1 activation leads to the suppression in the membrane translocation of Rac1 as well as p38, thus indicating that the LPS-elicited p38 membrane recruitment for TACE phosphorylation requires colocalization with Rac1. Hence, our findings imply that Rac1 membrane translocation serves as an essential platform for the localization of p38 with TACE, TGF-α ectodomain shedding, and the EGFR activation.
KEYWORDS
P. gingivalis LPS, Oral Mucosa, p38 MAPK, TGF-α, TACE Activation, Rac1, EGFR Transactivation
P. gingivalis LPS, Oral Mucosa, p38 MAPK, TGF-α, TACE Activation, Rac1, EGFR Transactivation
Cite this paper
Slomiany, B. and Slomiany, A. (2015) Porphyromonas gingivalis-Stimulated TACE Activation for TGF-α Ectodomain Shedding and EGFR Transactivation in Salivary Gland Cells Requires Rac1-Dependent p38 MAPK Membrane Localization. Journal of Biosciences and Medicines, 3, 42-53. doi: 10.4236/jbm.2015.311005.
Slomiany, B. and Slomiany, A. (2015) Porphyromonas gingivalis-Stimulated TACE Activation for TGF-α Ectodomain Shedding and EGFR Transactivation in Salivary Gland Cells Requires Rac1-Dependent p38 MAPK Membrane Localization. Journal of Biosciences and Medicines, 3, 42-53. doi: 10.4236/jbm.2015.311005.
References
[1] Nonnenmacher, C., Mutters, R. and deJacoby, L.F. (2001) Microbiological Characteristics of Subgingival Microbiota in Adult Periodontitis, Localized Juvenile Periodontitis and Rapidly Progressive Periodontitis Subjects. Clinical Microbiology and Infection, 7, 213-217.
http://dx.doi.org/10.1046/j.1469-0691.2001.00210.x [2] Wang, P.L. and Ohura, K. (2002) Porphyromonas gingivalis Lipopolysaccharide Signaling in Gingival Fibroblasts-CD14 and Toll-Like Receptors. Critical Reviews in Oral Biology and Medicine, 13, 132-142.
http://dx.doi.org/10.1177/154411130201300204 [3] Dareau, R.P., Arbabi, S., Gracia, I., Bainbridge, B. and Maier, R.V. (2002) Porphyromonas gingivalis Lipopolysaccharide Is Both Agonist and Antagonist for p38 Mitogen-Activated Protein Kinase Activation. Infection and Immunity, 70, 1867-1873.
http://dx.doi.org/10.1128/IAI.70.4.1867-1873.2002 [4] Slomiany, B.L. and Slomiany, A. (2007) Alteration by Indomethacin in Proinflammatory Consequences of Salivary Gland Cytosolic Phospholipase A2 Activation by Porphyromonas gingivalis: Role of Leptin. Journal of Applied Research, 7, 127-136. [5] Kawai, T. and Akira, S. (2010) The Role of Pattern-Recognition Receptors in Innate Immunity: Update on Toll-Like Receptors. Nature Immunology, 11, 373-384. http://dx.doi.org/10.1038/ni.1863 [6] Slomiany, B.L. and Slomiany, A. (2011) Ghrelin-Induced cSrc Activation through Constitutive Nitric Oxide Synthase-Dependent S-Nitrosylation in Modulation of Salivary Gland Acinar Cell Inflammatory Responses to Porphyromonas gingivalis. American Journal of Molecular Biology, 2, 43-51.
http://dx.doi.org/10.4236/ajmb.2011.12006 [7] Carpenter, S. and O’Neill, L.A.J. (2009) Recent Insights into the Structure of Toll-Like Receptors and Post-Translational Modifications of Their Associated Signaling Proteins. Biochemical Journal, 422, 1-10.
http://dx.doi.org/10.1042/BJ20090616 [8] Garrington, P.T. and Johnson, G.L. (1999) Organization and Regulation of Mitogen-Activated Protein Kinases Signaling Pathways. Current Opinion in Cell Biology, 11, 211-218.
http://dx.doi.org/10.1016/S0955-0674(99)80028-3 [9] Cuadrado, A. and Nebreda, A.R. (2010) Mechanism and Function of p38 MAPK Signaling. Biochemical Journal, 429, 403-417.
http://dx.doi.org/10.1042/BJ20100323 [10] Grishin, A.V., Wang, J., Potoka, D.A., et al. (2006) Lipopolysaccharide Induces Cyclooxygenase-2 in Intestinal Epithelium via a Non-Canonical p38 MAPK Pathway. Journal of Immunology, 176, 580-588.
http://dx.doi.org/10.4049/jimmunol.176.1.580 [11] Slomiany, B.L. and Slomiany, A. (2013) Involvement of p38 MAPK-Dependent Activator Protein (AP-1) Activation in Modulation of Gastric Mucosal Inflammatory Responses to Helicobacter pylori by Ghrelin. Inflammopharmacology, 21, 67-78. http://dx.doi.org/10.1007/s10787-012-0141-9 [12] Finzi, L., Shao, M.X.G., Paye, F., Housset, C. and Nadel, J.A. (2009) Lipopolysaccharide Initiates a Positive Feedback of Epidermal Growth Factor Receptor Signaling by Prostaglandin E2 in Human Biliary Carcinoma Cells. The Journal of Immunology, 182, 2269-2276.
http://dx.doi.org/10.4049/jimmunol.0801768 [13] Hsu, D., Fukata, M., Hernandez, Y.G., Sotolongo, J.P., Goo, T., Maki, J., et al. (2010) Toll-Like Receptor 4 Differentially Regulates Epidermal Growth Factor-Related Growth Factors in Response to Intestinal Mucosal Injury. Laboratory Investigation, 90, 1295-1305.
http://dx.doi.org/10.1038/labinvest.2010.100 [14] McElroy, S.J., Hobbs, S., Kallen, M., Tejera, N., Rosen, M.J., Grishin, A., et al. (2012) Transactivation of EGFR by LPS Induces COX-2 Expression in Enterocytes. PLoS ONE, 7, e38373.
http://dx.doi.org/10.1371/journal.pone.0038373 [15] Slomiany, B.L. and Slomiany, A. (2013) Role of EGFR Transactivation in the Amplification of Helicobacter pylori- Elicited Induction in Gastric Mucosal Expression of COX-2 and iNOS. OA Inflammation, 1, 1.
http://dx.doi.org/10.13172/2052-787X-1-1-412 [16] Trussoni, C.E., Tabibian, J.H., Splinter, P.L. and O’Hara, S.P. (2015) Lipopolysaccharide (LPS)-Induced Biliary Epithelial Cell NRas Activation Requires Epidermal Growth Factor Receptor (EGFR). PLoS ONE, 10, e0125793.
http://dx.doi.org/10.1371/journal.pone.0125793 [17] Carpenter, G. (1999) Employment of the Epidermal Growth Factor Receptor in Growth Factor-Independent Signaling Pathways. Journal of Cell Biology, 146, 697-702.
http://dx.doi.org/10.1083/jcb.146.4.697 [18] Ohsu, H., Dempsey, P. and Eguchi, S. (2006) ADAMs as Mediators of EGF Receptor Transactivation by G Protein-Coupled Receptors. American Journal of Cell Physiology, 291, C1-C10.
http://dx.doi.org/10.1152/ajpcell.00620.2005 [19] Slomiany, B.L. and Slomiany, A. (2004) Porphyromonas gingivalis Lipopolysaccharide-Induced Up-Regulation in Endothelin-1 Interferes with Salivary Mucin Synthesis via Epidermal Growth Factor Receptor Transactivation. IUBMB Life, 56, 601-607.
http://dx.doi.org/10.1080/15216540400020361 [20] Bergin, D.A., Greene, C.M., Sterchi, E.E., Kenna, C., Geraghty, P., Belaaouaj, A., et al. (2008) Activation of the Epidermal Growth Factor Receptor (EGFR) by a Novel Metalloprotease Pathway. Journal of Biological Chemistry, 283, 31736-31744.
http://dx.doi.org/10.1074/jbc.M803732200 [21] Xu, P. and Derynck, R. (2010) Direct Activation of TACE-Mediated Ectodomain Shedding by p38 MAP Kinase Regulates EGF Receptor-Dependent Cell Proliferation. Molecular Cell, 37, 551-566.
http://dx.doi.org/10.1016/j.molcel.2010.01.034 [22] Slomiany, B.L. and Slomiany, A. (2000) Aspirin Ingestion Impairs Oral Mucosal Ulcer Healing by Inducing Membrane-Bound Tumor Necrosis Factor-α Release. IUBMB Life, 50, 391-395. [23] Kong, L. and Ge, B.X. (2008) MyD88-Independent Activation of a Novel Actin-Cdc42/Rac Pathway Is Required for Toll-Like Receptor-Stimulated Phagocytosis. Cell Research, 18, 745-755.
http://dx.doi.org/10.1038/cr.2008.65 [24] Yao, H.Y., Chen, L.H., Wang, J.Y., Wang, J.R., Chen, J.Q., Xie, Q.M., et al. (2011) Inhibition of Rac Activity Alleviates Lipopolysaccharide-Induced Acute Pulmonary Injury in Mice. Biochimica et Biophysica Acta, 1810, 666-674.
http://dx.doi.org/10.1016/j.bbagen.2011.03.020 [25] Slomiany, B.L. and Slomiany, A. (2015) Porphyromonas gingivalis-Induced GEF Dock180 Activation by Src/PKCδ-Dependent Phosphorylation Mediates PLCγ2 Amplification in Salivary Gland Acinar Cells: Effect of Ghrelin. Journal of Biosciences and Medicines, 3, 66-77.
http://dx.doi.org/10.4236/jbm.2015.37008 [26] Slomiany, A. and Slomiany, B.L. (2012) Phosphatidylglycerol-Containing ER-Transport Vesicles Built and Restore Outer Mitochondrial Membrane and Deliver Nuclear DNA Translation Products to Generate Cardiolipin in the Inner Mitochondrial Membrane. Advances in Biological Chemistry, 2,132-145. http://dx.doi.org/10.4236/abc.2012.22016 [27] Slomiany, B.L. and Slomiany, A. (2010) Suppression by Ghrelin of Porphyromonas gingivalis-Induced Constitutive Nitric Oxide Synthase S-Nitrosylation and Apoptosis in Salivary Gland Acinar Cells. Journal of Signal Transduction, 2010, Article ID: 643642.
http://dx.doi.org/10.1155/2010/643642 [28] Kenny, P.A. and Bisseli, M.J. (2007) Targeting TACE-Dependent EGFR Ligand Shedding in Brest Cancer. Journal of Clinical Investigations, 117, 337-345.
http://dx.doi.org/10.1172/JCI29518 [29] Li, C., Hu, Y., Sturm, G., Wick, G. and Xu, Q. (2000) Ras/Rac-Dependent Activation of p38 Mitogen-Activated Protein Kinase in Smooth Muscle Cells Stimulated by Cyclic Strain Stress. Arteriosclerosis, Thrombosis, and Vascular Biology, 20, e1-e9.
http://dx.doi.org/10.1161/01.ATV.20.3.e1 [30] Wennerberg, K., Rossman, K.L. and Der, C.J. (2005) The Ras Superfamily at Glance. Journal of Cell Science, 118, 843-846.
http://dx.doi.org/10.1242/jcs.01660 [31] Parri, M. and Chiarugi, P. (2010) Rac and Rho GTPases in Cancer Cell Motility Control. Cell Communication and Signaling, 8, 23-37.
http://dx.doi.org/10.1186/1478-811X-8-23 [32] Walliser, C., Retlich, M., Harris, R., Everett, K.L., Josephs, M.B., Vatter, P., et al. (2008) Rac Regulates Its Effector Phospholipase Cγ2 through Interaction with a Split Pleckstrin Homology Domain. Journal of Biological Chemistry, 283, 30351-30362.
http://dx.doi.org/10.1074/jbc.M803316200 [33] Slomiany, B.L. and Slomiany, A. (2015) Mechanism of Rac1-Induced Amplification in Gastric Mucosal Phospholipase Cγ2 Activation in Response to Helicobacter pylori: Modulatory Effect of Ghrelin. Inflammopharmacology, 23, 101-109.
http://dx.doi.org/10.1007/s10787-015-0231-6 [34] Murai, T., Miyauchi, T., Yanagida, T. and Sako, Y. (2006) Epidermal Growth Factor-Regulated Activation of Rac GTPase Enhances CD44 Cleavage by Metalloprotease Disintegrin ADAM10. Biochemical Journal, 395, 65-71.
http://dx.doi.org/10.1042/BJ20050582
[1] Nonnenmacher, C., Mutters, R. and deJacoby, L.F. (2001) Microbiological Characteristics of Subgingival Microbiota in Adult Periodontitis, Localized Juvenile Periodontitis and Rapidly Progressive Periodontitis Subjects. Clinical Microbiology and Infection, 7, 213-217.
http://dx.doi.org/10.1046/j.1469-0691.2001.00210.x [2] Wang, P.L. and Ohura, K. (2002) Porphyromonas gingivalis Lipopolysaccharide Signaling in Gingival Fibroblasts-CD14 and Toll-Like Receptors. Critical Reviews in Oral Biology and Medicine, 13, 132-142.
http://dx.doi.org/10.1177/154411130201300204 [3] Dareau, R.P., Arbabi, S., Gracia, I., Bainbridge, B. and Maier, R.V. (2002) Porphyromonas gingivalis Lipopolysaccharide Is Both Agonist and Antagonist for p38 Mitogen-Activated Protein Kinase Activation. Infection and Immunity, 70, 1867-1873.
http://dx.doi.org/10.1128/IAI.70.4.1867-1873.2002 [4] Slomiany, B.L. and Slomiany, A. (2007) Alteration by Indomethacin in Proinflammatory Consequences of Salivary Gland Cytosolic Phospholipase A2 Activation by Porphyromonas gingivalis: Role of Leptin. Journal of Applied Research, 7, 127-136. [5] Kawai, T. and Akira, S. (2010) The Role of Pattern-Recognition Receptors in Innate Immunity: Update on Toll-Like Receptors. Nature Immunology, 11, 373-384. http://dx.doi.org/10.1038/ni.1863 [6] Slomiany, B.L. and Slomiany, A. (2011) Ghrelin-Induced cSrc Activation through Constitutive Nitric Oxide Synthase-Dependent S-Nitrosylation in Modulation of Salivary Gland Acinar Cell Inflammatory Responses to Porphyromonas gingivalis. American Journal of Molecular Biology, 2, 43-51.
http://dx.doi.org/10.4236/ajmb.2011.12006 [7] Carpenter, S. and O’Neill, L.A.J. (2009) Recent Insights into the Structure of Toll-Like Receptors and Post-Translational Modifications of Their Associated Signaling Proteins. Biochemical Journal, 422, 1-10.
http://dx.doi.org/10.1042/BJ20090616 [8] Garrington, P.T. and Johnson, G.L. (1999) Organization and Regulation of Mitogen-Activated Protein Kinases Signaling Pathways. Current Opinion in Cell Biology, 11, 211-218.
http://dx.doi.org/10.1016/S0955-0674(99)80028-3 [9] Cuadrado, A. and Nebreda, A.R. (2010) Mechanism and Function of p38 MAPK Signaling. Biochemical Journal, 429, 403-417.
http://dx.doi.org/10.1042/BJ20100323 [10] Grishin, A.V., Wang, J., Potoka, D.A., et al. (2006) Lipopolysaccharide Induces Cyclooxygenase-2 in Intestinal Epithelium via a Non-Canonical p38 MAPK Pathway. Journal of Immunology, 176, 580-588.
http://dx.doi.org/10.4049/jimmunol.176.1.580 [11] Slomiany, B.L. and Slomiany, A. (2013) Involvement of p38 MAPK-Dependent Activator Protein (AP-1) Activation in Modulation of Gastric Mucosal Inflammatory Responses to Helicobacter pylori by Ghrelin. Inflammopharmacology, 21, 67-78. http://dx.doi.org/10.1007/s10787-012-0141-9 [12] Finzi, L., Shao, M.X.G., Paye, F., Housset, C. and Nadel, J.A. (2009) Lipopolysaccharide Initiates a Positive Feedback of Epidermal Growth Factor Receptor Signaling by Prostaglandin E2 in Human Biliary Carcinoma Cells. The Journal of Immunology, 182, 2269-2276.
http://dx.doi.org/10.4049/jimmunol.0801768 [13] Hsu, D., Fukata, M., Hernandez, Y.G., Sotolongo, J.P., Goo, T., Maki, J., et al. (2010) Toll-Like Receptor 4 Differentially Regulates Epidermal Growth Factor-Related Growth Factors in Response to Intestinal Mucosal Injury. Laboratory Investigation, 90, 1295-1305.
http://dx.doi.org/10.1038/labinvest.2010.100 [14] McElroy, S.J., Hobbs, S., Kallen, M., Tejera, N., Rosen, M.J., Grishin, A., et al. (2012) Transactivation of EGFR by LPS Induces COX-2 Expression in Enterocytes. PLoS ONE, 7, e38373.
http://dx.doi.org/10.1371/journal.pone.0038373 [15] Slomiany, B.L. and Slomiany, A. (2013) Role of EGFR Transactivation in the Amplification of Helicobacter pylori- Elicited Induction in Gastric Mucosal Expression of COX-2 and iNOS. OA Inflammation, 1, 1.
http://dx.doi.org/10.13172/2052-787X-1-1-412 [16] Trussoni, C.E., Tabibian, J.H., Splinter, P.L. and O’Hara, S.P. (2015) Lipopolysaccharide (LPS)-Induced Biliary Epithelial Cell NRas Activation Requires Epidermal Growth Factor Receptor (EGFR). PLoS ONE, 10, e0125793.
http://dx.doi.org/10.1371/journal.pone.0125793 [17] Carpenter, G. (1999) Employment of the Epidermal Growth Factor Receptor in Growth Factor-Independent Signaling Pathways. Journal of Cell Biology, 146, 697-702.
http://dx.doi.org/10.1083/jcb.146.4.697 [18] Ohsu, H., Dempsey, P. and Eguchi, S. (2006) ADAMs as Mediators of EGF Receptor Transactivation by G Protein-Coupled Receptors. American Journal of Cell Physiology, 291, C1-C10.
http://dx.doi.org/10.1152/ajpcell.00620.2005 [19] Slomiany, B.L. and Slomiany, A. (2004) Porphyromonas gingivalis Lipopolysaccharide-Induced Up-Regulation in Endothelin-1 Interferes with Salivary Mucin Synthesis via Epidermal Growth Factor Receptor Transactivation. IUBMB Life, 56, 601-607.
http://dx.doi.org/10.1080/15216540400020361 [20] Bergin, D.A., Greene, C.M., Sterchi, E.E., Kenna, C., Geraghty, P., Belaaouaj, A., et al. (2008) Activation of the Epidermal Growth Factor Receptor (EGFR) by a Novel Metalloprotease Pathway. Journal of Biological Chemistry, 283, 31736-31744.
http://dx.doi.org/10.1074/jbc.M803732200 [21] Xu, P. and Derynck, R. (2010) Direct Activation of TACE-Mediated Ectodomain Shedding by p38 MAP Kinase Regulates EGF Receptor-Dependent Cell Proliferation. Molecular Cell, 37, 551-566.
http://dx.doi.org/10.1016/j.molcel.2010.01.034 [22] Slomiany, B.L. and Slomiany, A. (2000) Aspirin Ingestion Impairs Oral Mucosal Ulcer Healing by Inducing Membrane-Bound Tumor Necrosis Factor-α Release. IUBMB Life, 50, 391-395. [23] Kong, L. and Ge, B.X. (2008) MyD88-Independent Activation of a Novel Actin-Cdc42/Rac Pathway Is Required for Toll-Like Receptor-Stimulated Phagocytosis. Cell Research, 18, 745-755.
http://dx.doi.org/10.1038/cr.2008.65 [24] Yao, H.Y., Chen, L.H., Wang, J.Y., Wang, J.R., Chen, J.Q., Xie, Q.M., et al. (2011) Inhibition of Rac Activity Alleviates Lipopolysaccharide-Induced Acute Pulmonary Injury in Mice. Biochimica et Biophysica Acta, 1810, 666-674.
http://dx.doi.org/10.1016/j.bbagen.2011.03.020 [25] Slomiany, B.L. and Slomiany, A. (2015) Porphyromonas gingivalis-Induced GEF Dock180 Activation by Src/PKCδ-Dependent Phosphorylation Mediates PLCγ2 Amplification in Salivary Gland Acinar Cells: Effect of Ghrelin. Journal of Biosciences and Medicines, 3, 66-77.
http://dx.doi.org/10.4236/jbm.2015.37008 [26] Slomiany, A. and Slomiany, B.L. (2012) Phosphatidylglycerol-Containing ER-Transport Vesicles Built and Restore Outer Mitochondrial Membrane and Deliver Nuclear DNA Translation Products to Generate Cardiolipin in the Inner Mitochondrial Membrane. Advances in Biological Chemistry, 2,132-145. http://dx.doi.org/10.4236/abc.2012.22016 [27] Slomiany, B.L. and Slomiany, A. (2010) Suppression by Ghrelin of Porphyromonas gingivalis-Induced Constitutive Nitric Oxide Synthase S-Nitrosylation and Apoptosis in Salivary Gland Acinar Cells. Journal of Signal Transduction, 2010, Article ID: 643642.
http://dx.doi.org/10.1155/2010/643642 [28] Kenny, P.A. and Bisseli, M.J. (2007) Targeting TACE-Dependent EGFR Ligand Shedding in Brest Cancer. Journal of Clinical Investigations, 117, 337-345.
http://dx.doi.org/10.1172/JCI29518 [29] Li, C., Hu, Y., Sturm, G., Wick, G. and Xu, Q. (2000) Ras/Rac-Dependent Activation of p38 Mitogen-Activated Protein Kinase in Smooth Muscle Cells Stimulated by Cyclic Strain Stress. Arteriosclerosis, Thrombosis, and Vascular Biology, 20, e1-e9.
http://dx.doi.org/10.1161/01.ATV.20.3.e1 [30] Wennerberg, K., Rossman, K.L. and Der, C.J. (2005) The Ras Superfamily at Glance. Journal of Cell Science, 118, 843-846.
http://dx.doi.org/10.1242/jcs.01660 [31] Parri, M. and Chiarugi, P. (2010) Rac and Rho GTPases in Cancer Cell Motility Control. Cell Communication and Signaling, 8, 23-37.
http://dx.doi.org/10.1186/1478-811X-8-23 [32] Walliser, C., Retlich, M., Harris, R., Everett, K.L., Josephs, M.B., Vatter, P., et al. (2008) Rac Regulates Its Effector Phospholipase Cγ2 through Interaction with a Split Pleckstrin Homology Domain. Journal of Biological Chemistry, 283, 30351-30362.
http://dx.doi.org/10.1074/jbc.M803316200 [33] Slomiany, B.L. and Slomiany, A. (2015) Mechanism of Rac1-Induced Amplification in Gastric Mucosal Phospholipase Cγ2 Activation in Response to Helicobacter pylori: Modulatory Effect of Ghrelin. Inflammopharmacology, 23, 101-109.
http://dx.doi.org/10.1007/s10787-015-0231-6 [34] Murai, T., Miyauchi, T., Yanagida, T. and Sako, Y. (2006) Epidermal Growth Factor-Regulated Activation of Rac GTPase Enhances CD44 Cleavage by Metalloprotease Disintegrin ADAM10. Biochemical Journal, 395, 65-71.
http://dx.doi.org/10.1042/BJ20050582