22. Tu H, Zhou Z, Liang Q, Li Z, Li D, et al. (2009) CXCR4 and SDF-1 production are stimulated by hepatocyte growth factor and promote glioma cell invasion. Onkologie 32: 331–336. 23. Chianale F, Rainero E, Cianflone C, Bettio V, Pighini A, et al. Diacylglycerol kinase alpha mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI. Proc Natl Acad Sci U S A 107: 4182–4187. 24. Liu WS, Heckman CA (1998) The sevenfold way of PKC regulation. Cell Signal 10: 529–542. 25. Petit I, Goichberg P, Spiegel A, Peled A, Brodie C, et al. (2005) Atypical PKC- zeta regulates SDF-1-mediated migration and development of human CD34+ progenitor cells. J Clin Invest 115: 168–176. 26. Duran A, Rodriguez A, Martin P, Serrano M, Flores JM, et al. (2004) Crosstalk between PKCzeta and the IL4/Stat6 pathway during T-cell-mediated hepatitis. Embo J 23: 4595–4605. 27. Sun R, Gao P, Chen L, Ma D, Wang J, et al. (2005) Protein kinase C zeta is required for epidermal growth factor-induced chemotaxis of human breast cancer cells. Cancer Res 65: 1433–1441. 28. Vasavada RC, Wang L, Fujinaka Y, Takane KK, Rosa TC, et al. (2007) Protein kinase C-zeta activation markedly enhances beta-cell proliferation: an essential role in growth factor mediated beta-cell mitogenesis. Diabetes 56: 2732–2743. 29. Stuart KA, Riordan SM, Lidder S, Crostella L, Williams R, et al. (2000) Hepatocyte growth factor/scatter factor-induced intracellular signalling. Int J Exp Pathol 81: 17–30. 30. Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, et al. (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6: 17–32. 31. Gschwendt M, Kittstein W, Johannes FJ (1998) Differential effects of suramin on protein kinase C isoenzymes. A novel tool for discriminating protein kinase C activities. FEBS Lett 421: 165–168. 32. Royal I, Lamarche-Vane N, Lamorte L, Kaibuchi K, Park M (2000) Activation of cdc42, rac, PAK, and rho-kinase in response to hepatocyte growth factor differentially regulates epithelial cell colony spreading and dissociation. Mol Biol Cell 11: 1709–1725. 33. Tunggal JA, Helfrich I, Schmitz A, Schwarz H, Gunzel D, et al. (2005) E- cadherin is essential for in vivo epidermal barrier function by regulating tight junctions. Embo J 24: 1146–1156. 34. Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y (2004) Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A 101: 7618–7623. 35. Haribabu B, Richardson RM, Fisher I, Sozzani S, Peiper SC, et al. (1997) Regulation of human chemokine receptors CXCR4. Role of phosphorylation in desensitization and internalization. J Biol Chem 272: 28726–28731. 36. Cheng ZJ, Zhao J, Sun Y, Hu W, Wu YL, et al. (2000) beta-arrestin differentially regulates the chemokine receptor CXCR4-mediated signaling and receptor internalization, and this implicates multiple interaction sites between beta- arrestin and CXCR4. J Biol Chem 275: 2479–2485. 37. Woerner BM, Warrington NM, Kung AL, Perry A, Rubin JB (2005) Widespread CXCR4 activation in astrocytomas revealed by phospho- CXCR4-specific antibodies. Cancer Res 65: 11392–11399. 38. Beviglia L, Matsumoto K, Lin CS, Ziober BL, Kramer RH (1997) Expression of the c-Met/HGF receptor in human breast carcinoma: correlation with tumor progression. Int J Cancer 74: 301–309. 39. Jiang WG, Davies G, Martin TA, Parr C, Watkins G, et al. (2006) Expression of membrane type-1 matrix metalloproteinase, MT1-MMP in human breast cancer and its impact on invasiveness of breast cancer cells. Int J Mol Med 17: 583–590. 40. Kim JI, Cordova AC, Hirayama Y, Madri JA, Sumpio BE (2008) Differential effects of shear stress and cyclic strain on Sp1 phosphorylation by protein kinase Czeta modulates membrane type 1-matrix metalloproteinase in endothelial cells. Endothelium 15: 33–42. PKCf Induced by HGF Increases CXCR4 Expression 41. Bartolome RA, Ferreiro S, Miquilena-Colina ME, Martinez-Prats L, Soto- Montenegro ML, et al. (2009) The chemokine receptor CXCR4 and the metalloproteinase MT1-MMP are mutually required during melanoma metastasis to lungs. Am J Pathol 174: 602–612. 42. Shirvaikar N, Marquez-Curtis LA, Ratajczak MZ, Janowska-Wieczorek A. Hyaluronic acid and thrombin upregulate MT1-MMP through PI3K and Rac-1 signaling and prime the homing-related responses of cord blood hematopoietic stem/progenitor cells. Stem Cells Dev 20: 19–30. 43. Zhuge Y, Xu J (2001) Rac1 mediates type I collagen-dependent MMP-2 activation. role in cell invasion across collagen barrier. J Biol Chem 276: 16248–16256. 44. Bourbon NA, Yun J, Kester M (2000) Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex. J Biol Chem 275: 35617–35623. 45. Chung CY, Potikyan G, Firtel RA (2001) Control of cell polarity and chemotaxis by Akt/PKB and PI3 kinase through the regulation of PAKa. Mol Cell 7: 937–947. 46. Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF, et al. (2001) Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidy- linositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc Natl Acad Sci U S A 98: 247–252. 47. Higuchi M, Masuyama N, Fukui Y, Suzuki A, Gotoh Y (2001) Akt mediates Rac/Cdc42-regulated cell motility in growth factor-stimulated cells and in invasive PTEN knockout cells. Curr Biol 11: 1958–1962. 48. Kanazawa S, Fujiwara T, Matsuzaki S, Shingaki K, Taniguchi M, et al. bFGF regulates PI3-kinase-Rac1-JNK pathway and promotes fibroblast migration in wound healing. PLoS One 5: e12228. 49. Manning G, Plowman GD, Hunter T, Sudarsanam S (2002) Evolution of protein kinase signaling from yeast to man. Trends Biochem Sci 27: 514–520. 50. Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, et al. (2000) Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19: 3013–3020. 51. Sulpice E, Ding S, Muscatelli-Groux B, Berge M, Han ZC, et al. (2009) Cross- talk between the VEGF-A and HGF signalling pathways in endothelial cells. Biol Cell 101: 525–539. 52. Wysoczynski M, Reca R, Ratajczak J, Kucia M, Shirvaikar N, et al. (2005) Incorporation of CXCR4 into membrane lipid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient. Blood 105: 40–48. 53. Noda Y, Takeya R, Ohno S, Naito S, Ito T, et al. (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 Cells 6: 107–119. 54. Ramos-Nino ME, Blumen SR, Sabo-Attwood T, Pass H, Carbone M, et al. (2008) HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway. Am J Respir Cell Mol Biol 38: 209–217. 55. Webb CP, Taylor GA, Jeffers M, Fiscella M, Oskarsson M, et al. (1998) Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/ metastasis. Oncogene 17: 2019–2025. 56. McBain VA, Forrester JV, McCaig CD (2003) HGF, MAPK, and a small physiological electric field interact during corneal epithelial cell migration. Invest Ophthalmol Vis Sci 44: 540–547. 57. Giagulli C, Scarpini E, Ottoboni L, Narumiya S, Butcher EC, et al. (2004) RhoA and zeta PKC control distinct modalities of LFA-1 activation by chemokines: critical role of LFA-1 affinity triggering in lymphocyte in vivo homing. Immunity 20: 25–35. 58. Yamazaki D, Kurisu S, Takenawa T (2009) Involvement of Rac and Rho signaling in cancer cell motility in 3D substrates. Oncogene 28: 1570–1583. 59. Gong C, Yao H, Liu Q, Chen J, Shi J, et al. Markers of tumor-initiating cells predict chemoresistance in breast cancer. PLoS One 5: e15630. PLoS ONE | www.plosone.org 16 January 2012 | Volume 7 | Issue 1 | e29124