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Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer.
Dushyanthen S, Teo ZL, Caramia F, Savas P, Mintoff CP, Virassamy B, Henderson MA, Luen SJ, Mansour M, Kershaw MH, Trapani JA, Neeson PJ, Salgado R, McArthur GA, Balko JM, Beavis PA, Darcy PK, Loi S
(2017) Nat Commun 8: 606
MeSH Terms: 4-1BB Ligand, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Female, Humans, Immunotherapy, Lymphocytes, Tumor-Infiltrating, MAP Kinase Kinase 1, MAP Kinase Kinase 2, MAP Kinase Signaling System, Mammary Neoplasms, Animal, Mice, OX40 Ligand, Protein Kinase Inhibitors, Pyridones, Pyrimidinones, T-Lymphocyte Subsets, T-Lymphocytes, Triple Negative Breast Neoplasms
Show Abstract · Added March 14, 2018
The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo. This effect is dependent upon increased downstream p38/JNK pathway activation. Taken together, our data suggest that although Ras/MAPK pathway inhibition can increase tumor immunogenicity, the negative impact on T-cell activity is functionally important. This undesirable impact is effectively prevented by combination with T-cell immune agonist immunotherapies resulting in superior therapeutic efficacy.MEK inhibition in breast cancer is associated with increased tumour infiltrating lymphocytes (TILs), however, MAPK activity is required for T cells function. Here the authors show that TILs activity following MEK inhibition can be enhanced by agonist immunotherapy resulting in synergic therapeutic effects.
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21 MeSH Terms
Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor.
Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD
(2013) J Clin Oncol 31: 482-9
MeSH Terms: Adult, Aged, Antineoplastic Agents, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Male, Melanoma, Middle Aged, Mutation, Neoplasm Staging, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones, Skin Neoplasms, Treatment Outcome
Show Abstract · Added March 20, 2014
PURPOSE - BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma.
PATIENTS AND METHODS - This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily.
RESULTS - In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed.
CONCLUSION - Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.
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19 MeSH Terms
Cadherin-11 regulates cell-cell tension necessary for calcific nodule formation by valvular myofibroblasts.
Hutcheson JD, Chen J, Sewell-Loftin MK, Ryzhova LM, Fisher CI, Su YR, Merryman WD
(2013) Arterioscler Thromb Vasc Biol 33: 114-20
MeSH Terms: Actins, Animals, Aortic Valve, Cadherins, Calcinosis, Cell Communication, Cells, Cultured, Female, Heart Valve Diseases, Humans, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Male, Middle Aged, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Morphogenesis, Myofibroblasts, Phosphorylation, Protein Kinase Inhibitors, RNA Interference, Signal Transduction, Stress, Mechanical, Swine, Transfection, Transforming Growth Factor beta1
Show Abstract · Added December 10, 2013
OBJECTIVE - Dystrophic calcific nodule formation in vitro involves differentiation of aortic valve interstitial cells (AVICs) into a myofibroblast phenotype. Interestingly, inhibition of the kinase MAPK Erk kinase (MEK)1/2 prevents calcific nodule formation despite leading to myofibroblast activation of AVICs, indicating the presence of an additional mechanotransductive component required for calcific nodule morphogenesis. In this study, we assess the role of transforming growth factor β1-induced cadherin-11 expression in calcific nodule formation.
METHODS AND RESULTS - As shown previously, porcine AVICs treated with transforming growth factor β1 before cyclic strain exhibit increased myofibroblast activation and significant calcific nodule formation. In addition to an increase in contractile myofibroblast markers, transforming growth factor β1-treated AVICs exhibit significantly increased expression of cadherin-11. This expression is inhibited by the addition of U0126, a specific MEK1/2 inhibitor. The role of increased cadherin-11 is revealed through a wound assay, which demonstrates increased intercellular tension in transforming growth factor β1-treated AVICs possessing cadherin-11. Furthermore, when small interfering RNA is used to knockdown cadherin-11, calcific nodule formation is abrogated, indicating that robust cell-cell connections are necessary in generating tension for calcific nodule morphogenesis. Finally, we demonstrate enrichment of cadherin-11 in human calcified leaflets.
CONCLUSIONS - These results indicate the necessity of cadherin-11 for dystrophic calcific nodule formation, which proceeds through an Erk1/2-dependent pathway.
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26 MeSH Terms
Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma.
Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, Middleton M, Cantarini M, Zazulina V, Kemsley K, Dummer R
(2012) Clin Cancer Res 18: 555-67
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Alkylating, Benzimidazoles, DNA Mutational Analysis, Dacarbazine, Disease-Free Survival, Drug Substitution, Female, Humans, Kaplan-Meier Estimate, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Male, Melanoma, Middle Aged, Mutation, Neoplasm Staging, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins p21(ras), Temozolomide, Treatment Outcome, Young Adult
Show Abstract · Added March 20, 2014
PURPOSE - To compare the efficacy and tolerability of the mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) 1/2 inhibitor selumetinib versus temozolomide in chemotherapy-naive patients with unresectable stage III/IV melanoma.
EXPERIMENTAL DESIGN - This phase II, open-label, multicenter, randomized, parallel-group study examined the effect of 100 mg oral selumetinib twice daily in 28-day cycles versus oral temozolomide (200 mg/m(2)/d for 5 days, then 23 days off-treatment). The primary endpoint was progression-free survival.
RESULTS - Two hundred patients were randomized. Progression-free survival did not differ significantly between selumetinib and temozolomide (median time to event 78 and 80 days, respectively; hazard ratio, 1.07; 80% confidence interval, 0.86-1.32). Objective response was observed in six (5.8%) patients receiving selumetinib and nine (9.4%) patients in the temozolomide group. Among patients with BRAF mutations, objective responses were similar between selumetinib and temozolomide groups (11.1% and 10.7%, respectively). However, five of the six selumetinib partial responders were BRAF mutated. Frequently reported adverse events with selumetinib were dermatitis acneiform (papular pustular rash; 59.6%), diarrhea (56.6%), nausea (50.5%), and peripheral edema (40.4%), whereas nausea (64.2%), constipation (47.4%), and vomiting (44.2%) were reported with temozolomide.
CONCLUSIONS - No significant difference in progression-free survival was observed between patients with unresectable stage III/IV melanoma unselected for BRAF/NRAS mutations, who received therapy with selumetinib or temozolomide. Five of six patients with partial response to selumetinib had BRAF mutant tumors.
©2011 AACR.
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24 MeSH Terms
Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers.
Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, Kauh JS, O'Neil BH, Balsom S, Balint C, Liersemann R, Vasko VV, Bloomston M, Marsh W, Doyle LA, Ellison G, Grever M, Ringel MD, Villalona-Calero MA
(2011) J Clin Oncol 29: 2357-63
MeSH Terms: Adult, Aged, Benzimidazoles, Biliary Tract Neoplasms, Extracellular Signal-Regulated MAP Kinases, Female, Humans, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Male, Middle Aged, Mutation, Neoplasm Metastasis, Phosphorylation, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins p21(ras), ras Proteins
Show Abstract · Added March 11, 2014
PURPOSE - Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC.
PATIENTS AND METHODS - This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations.
RESULTS - Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response.
CONCLUSION - Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.
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19 MeSH Terms
Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma.
O'Neil BH, Goff LW, Kauh JS, Strosberg JR, Bekaii-Saab TS, Lee RM, Kazi A, Moore DT, Learoyd M, Lush RM, Sebti SM, Sullivan DM
(2011) J Clin Oncol 29: 2350-6
MeSH Terms: Aged, Benzimidazoles, Carcinoma, Hepatocellular, Female, Humans, Liver Neoplasms, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Male, Middle Aged
Show Abstract · Added March 11, 2014
PURPOSE Hepatocellular carcinoma (HCC) is a common and deadly malignancy with few systemic therapy options. The RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is activated in approximately 50% to 60% of HCCs and represents a potential target for therapy. Selumetinib is an orally available inhibitor of MEK tyrosine kinase activity. PATIENTS AND METHODS Patients with locally advanced or metastatic HCC who had not been treated with prior systemic therapy were enrolled on to the study. Patients were treated with selumetinib at its recommended phase II dose of 100 mg twice per day continuously. Cycle length was 21 days. Imaging was performed every two cycles. Biopsies were obtained at baseline and at steady-state in a subset of patients, and pharmacokinetic (PK) analysis was performed on all patients. Results Nineteen patients were enrolled, 17 of whom were evaluable for response. Most (82%) had Child-Pugh A cirrhosis. Toxicity was in line with other studies of selumetinib in noncirrhotic patients. PK parameters were also comparable to those in noncirrhotic patients. No radiographic response was observed in this group, and the study was stopped at the interim analysis. Of 11 patients with elevated α-fetoprotein, three (27%) had decreases of 50% or more. Median time to progression was 8 weeks. Inhibition of ERK phosphorylation was demonstrated by Western blotting. CONCLUSION In this study of selumetinib for patients with HCC, no radiographic responses were seen and time to progression was short, which suggests minimal single-agent activity despite evidence of suppression of target activation.
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10 MeSH Terms
Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis.
Tai YT, Fulciniti M, Hideshima T, Song W, Leiba M, Li XF, Rumizen M, Burger P, Morrison A, Podar K, Chauhan D, Tassone P, Richardson P, Munshi NC, Ghobrial IM, Anderson KC
(2007) Blood 110: 1656-63
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Bone Marrow Cells, Boronic Acids, Bortezomib, Cell Adhesion, Cell Differentiation, Cell Proliferation, Cell Survival, Cytotoxins, Dexamethasone, Dose-Response Relationship, Drug, Interleukin-6, Lenalidomide, Ligands, MAP Kinase Kinase 1, MAP Kinase Kinase 2, MAP Kinase Signaling System, Macrophage Colony-Stimulating Factor, Mice, Mice, SCID, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Multiple Myeloma, Neoplasm Transplantation, Osteoclasts, Phosphorylcholine, Pyrazines, RANK Ligand, Stromal Cells, Thalidomide, Transplantation, Heterologous, Tumor Cells, Cultured, Xenograft Model Antitumor Assays
Show Abstract · Added November 7, 2019
Activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signaling cascade mediates human multiple myeloma (MM) growth and survival triggered by cytokines and adhesion to bone marrow stromal cells (BMSCs). Here, we examined the effect of AZD6244 (ARRY-142886), a novel and specific MEK1/2 inhibitor, on human MM cell growth in the bone marrow (BM) milieu. AZD6244 blocks constitutive and cytokine-stimulated ERK1/2 phosphorylation and inhibits proliferation and survival of human MM cell lines and patient MM cells, regardless of sensitivity to conventional chemotherapy. Importantly, AZD6244 (200 nM) induces apoptosis in patient MM cells, even in the presence of exogenous interleukin-6 or BMSCs associated with triggering of caspase 3 activity. AZD6244 sensitizes MM cells to both conventional (dexamethasone) and novel (perifosine, lenalidomide, and bortezomib) therapies. AZD6244 down-regulates the expression/secretion of osteoclast (OC)-activating factors from MM cells and inhibits in vitro differentiation of MM patient PBMCs to OCs induced by ligand for receptor activator of NF-kappaB (RANKL) and macrophage-colony stimulating factor (M-CSF). Finally, AZD6244 inhibits tumor growth and prolongs survival in vivo in a human plasmacytoma xenograft model. Taken together, these results show that AZD6244 targets both MM cells and OCs in the BM microenvironment, providing the preclinical framework for clinical trials to improve patient outcome in MM.
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MeSH Terms
Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by protein serine/threonine phosphatase 2A holoenzymes.
Adams DG, Coffee RL, Zhang H, Pelech S, Strack S, Wadzinski BE
(2005) J Biol Chem 280: 42644-54
MeSH Terms: Blotting, Western, Catalytic Domain, Cell Line, Dimerization, Enzyme Activation, Enzyme Inhibitors, Epitopes, Gene Expression Regulation, Enzymologic, Humans, Immunoblotting, Immunoprecipitation, Luciferases, MAP Kinase Kinase 1, MAP Kinase Kinase 2, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Phosphoprotein Phosphatases, Phosphorylation, Plasmids, Protein Phosphatase 2, Proto-Oncogene Proteins c-raf, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Serine, Signal Transduction, Tetracycline, Transfection
Show Abstract · Added December 10, 2013
Protein serine/threonine phosphatase 2A (PP2A) regulates a wide variety of cellular signal transduction pathways. The predominant form of PP2A in cells is a heterotrimeric holoenzyme consisting of a scaffolding (A) subunit, a regulatory (B) subunit, and a catalytic (C) subunit. Although PP2A is known to regulate Raf1-MEK1/2-ERK1/2 signaling at multiple steps in this pathway, the specific PP2A holoenzymes involved remain unclear. To address this question, we established tetracycline-inducible human embryonic kidney 293 cell lines for overexpression of FLAG-tagged Balpha/delta regulatory subunits by approximately 3-fold or knock-down of Balpha by greater than 70% compared with endogenous levels. The expression of functional epitope-tagged B subunits was confirmed by the detection of A and C subunits as well as phosphatase activity in FLAG immune complexes from extracts of cells overexpressing the FLAG-Balpha/delta subunit. Western analysis of the cell extracts using phosphospecific antibodies for MEK1/2 and ERK1/2 demonstrated that activation of these kinases in response to epidermal growth factor was markedly diminished in Balpha knock-down cells but elevated in Balpha- and Bdelta-overexpressing cells as compared with control cells. In parallel with the activation of MEK1/2 and ERK1/2, the inhibitory phosphorylation site of Raf1 (Ser-259) was dephosphorylated in cells overexpressing Balpha or Bdelta. Pharmacological inhibitor studies as well as reporter assays for ERK-dependent activation of the transcription factor Elk1 revealed that the PP2A holoenzymes ABalphaC and ABdeltaC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. Together these findings indicate that PP2A ABalphaC and ABdeltaC holoenzymes function as positive regulators of Raf1-MEK1/2-ERK1/2 signaling by targeting Raf1.
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28 MeSH Terms
Sulindac sulfide inhibits epidermal growth factor-induced phosphorylation of extracellular-regulated kinase 1/2 and Bad in human colon cancer cells.
Rice PL, Washington M, Schleman S, Beard KS, Driggers LJ, Ahnen DJ
(2003) Cancer Res 63: 616-20
MeSH Terms: Antineoplastic Agents, Butadienes, Carrier Proteins, Caspase Inhibitors, Caspases, Colonic Neoplasms, Enzyme Activation, Epidermal Growth Factor, Humans, MAP Kinase Kinase 1, MAP Kinase Kinase 2, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Nitriles, Phosphorylation, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Sulindac, Tumor Cells, Cultured, bcl-Associated Death Protein
Show Abstract · Added March 5, 2014
Colorectal cancer is the second leading cause of cancer death in the United States. Nonsteroidal anti-inflammatory drugs including sulindac are promising chemopreventive agents for colorectal cancer. Sulindac and selective cyclooxygenase (COX)-2 inhibitors cause regression of colonic polyps in familial polyposis patients. Sulindac induces apoptotic cell death in cancer cells in vitro and in vivo. In tumor cells, activation of extracellular-regulated kinase (ERK) 1/2 results in phosphorylation of several ERK1/2 effectors, including the proapoptotic protein Bad. Phosphorylation of Ser112 by ERK1/2 inactivates Bad and protects the tumor cell from apoptosis. Sulindac metabolites and other nonsteroidal anti-inflammatory drugs selectively inhibit ERK1/2 phosphorylation in human colon cancer cells. In this study we show that epidermal growth factor (EGF) strongly induces phosphorylation of ERK1/2 and Bad in HT29 colon cancer cells. EGF-stimulated phosphorylation of ERK and Bad is blocked by pretreatment with U0126, a selective MAP kinase kinase (MKK)1/2 inhibitor. Similarly, pretreatment with sulindac sulfide blocks the ability of EGF to induce ERK1/2 and Bad phosphorylation, but also down-regulates total Bad but not ERK1/2 protein levels. The ability of sulindac to block ERK1/2 signaling by the EGF receptor may account for at least part of its potent growth-inhibitory effects against cancer cells.
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23 MeSH Terms
PAK1 kinase is required for CXCL1-induced chemotaxis.
Wang D, Sai J, Carter G, Sachpatzidis A, Lolis E, Richmond A
(2002) Biochemistry 41: 7100-7
MeSH Terms: Animals, Calcium, Cell Line, Chemokine CXCL1, Chemokines, CXC, Chemotactic Factors, Chemotaxis, Enzyme Activation, Growth Substances, Humans, Intercellular Signaling Peptides and Proteins, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Mitogen-Activated Protein Kinase Kinases, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Rats, Signal Transduction, Tumor Cells, Cultured, cdc42 GTP-Binding Protein, p21-Activated Kinases
Show Abstract · Added May 30, 2013
The CXC subfamily of chemokines plays an important role in diverse processes, including inflammation, wound healing, growth regulation, angiogenesis, and tumorigenesis. The CXC chemokine CXCL1, or MGSA/GROalpha, is traditionally considered to be responsible for attracting leukocytes into sites of inflammation. To better understand the molecular mechanisms by which CXCL1 induces CXCR2-mediated chemotaxis, the signal transduction components involved in CXCL1-induced chemotaxis were examined. It is shown here that CXCL1 induces cdc42 and PAK1 activation in CXCR2-expressing HEK293 cells. Activation of the cdc42-PAK1 cascade is required for CXCL1-induced chemotaxis but not for CXCL1-induced intracellular Ca2+ mobilization. Moreover, CXCL1 activation of PAK1 is independent of ERK1/2 activation, a conclusion based on the observations that the inhibition of MEK-ERK activation by expression of dominant negative ERK or by the MEK inhibitor, PD98059, has no effect on CXCL1-induced PAK1 activation or CXCL1-induced chemotaxis.
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21 MeSH Terms