MAP kinases and cell migration

Huang, Cai; Jacobson, Ken; Schaller, Michael D.

doi:10.1242/jcs.01481

Cited by 986 publications

(891 citation statements)

References 132 publications

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“…Mammalian cells contain three major classes of MAPK: ERK, JNK, and p38. All three kinases have been shown to play crucial roles in cell migration by distinct mechanisms [35]. Our results confirm the importance of EKR, JNK and p38 MAPK also for b-defensin-induced chemotaxis of macrophages and mast cells.…”

Section: Discussionsupporting

confidence: 84%

β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

et al. 2007

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b-Defensins are natural peptide antibiotics whose immunomodulatory functions are poorly understood. In the present study, macrophages were found to migrate to human b-defensins (HBD)-1 to -4 using Ga i proteins as well as MAPK ERK, p38 and JNK as signal transducers. In addition, mast cells responded to HBD-1 to -4 with calcium fluxes as well as chemotaxis, which increased upon stimulation with IgE plus antigen or ionomycin. In contrast, human b-defensins were unable to induce migration of memory lymphocytes and dendritic cells (DC). Similar to HBD, the murine b-defensin (mBD)-8 mobilized macrophages and lacked the ability to recruit memory T cells. These findings were unexpected as CCR6 on memory T cells and DC has been previously observed to be a receptor for human b-defensins. In support of our findings, however, RBL-2H3 as well as 300.19 cells stably expressing CCR6 proved to be unresponsive to HBD-2 and -3. Intriguingly, our observation of a PKC-independent homologous desensitization between HBD-1 to -4 suggests a common receptor for HBD. In summary, chemoattraction of macrophages and mast cells is evolutionary conserved within the b-defensin family despite a considerable sequence variation and distinct antimicrobial activities. However, CCR6 is not a functional receptor for b-defensins.

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Section: Discussionsupporting

confidence: 84%

β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

et al. 2007

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“…This indicates that isoginkgetin could inhibit other pathways that regulate cell invasion. Although mitogen-activated protein kinases, such as ERK and p38, do not regulate MMP-9 expression in HT1080 cells, they have shown to be important for cell invasion and migration (29,30). Therefore, we examined the effect of isoginkgtin on mitogen-activated protein kinases and found that Results were statistically significant (*, P < 0.01) using Student's t test.…”

Section: Discussionmentioning

confidence: 95%

Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt–dependent matrix metalloproteinase-9 expression

Yoon

Shin

Lee³

et al. 2006

Molecular Cancer Therapeutics

105

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Matrix metalloproteinase (MMP)-9 plays a key role in tumor invasion. Inhibitors of MMP-9 were screened from Metasequoia glyptostroboides (Dawn redwood) and one potent inhibitor, isoginkgetin, a biflavonoid, was identified. Noncytotoxic levels of isoginkgetin decreased MMP-9 production profoundly, but up-regulated the level of tissue inhibitor of metalloproteinase (TIMP)-1, an inhibitor of MMP-9, in HT1080 human fibrosarcoma cells. The major mechanism of Ras-dependent MMP-9 production in HT1080 cells was phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor-KB (NF-KB) activation. Expression of dominant-active H-Ras and p85 (a subunit of PI3K) increased MMP-9 activity, whereas dominant-negative forms of these molecules decreased the level of MMP-9. H-Ras did not increase MMP-9 in the presence of a PI3K inhibitor, LY294002, and a NF-KB inhibitor, SN50. Further studies showed that isoginkgetin regulated MMP-9 production via PI3K/Akt/NF-KB pathway, as evidenced by the findings that isoginkgetin inhibited activities of both Akt and NF-KB. PI3K/Akt is a well-known key pathway for cell invasion, and isoginkgetin inhibited HT1080 tumor cell invasion substantially. Isoginkgetin was also quite effective in inhibiting the activities of Akt and MMP-9 in MDA-MB-231 breast carcinomas and B16F10 melanoma. Moreover, isoginkgetin treatment resulted in marked decrease in invasion of these cells. In summary, PI3K/ Akt is a major pathway for MMP-9 expression and isoginkgetin markedly decreased MMP-9 expression and invasion through inhibition of this pathway. This suggests that isoginkgetin could be a potential candidate as a therapeutic agent against tumor invasion. [Mol Cancer Ther 2006;5(11):2666 -75]

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“…MEK-ERK may regulate cell motility by preventing formation of extensive actin stress fibers via suppression of tropomyosin induction by TGF-b1 (Bakin et al, 2004) or inhibition of RhoA-Rho kinase pathway (Sahai et al, 2001;Pawlak and Helfman, 2002). JNK may regulate motility by modulating the dynamics of microtubules (Huang et al, 2004) or by affecting the assembly/ stability of focal adhesion complexes via phosphorylation of paxillin and Spir, a WASP family protein (reviewed by Huang et al (2004)). The role of JNK in TGF-b-mediated cell motility, however, is less defined, given that inhibition of JNK does not affect TGF-bmediated actin remodeling and epithelial to mesenchymal transition (EMT) (Bhowmick et al, 2001a;Bakin et al, 2002Bakin et al, , 2004Edlund et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells

2006

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Transforming growth factor beta 1 (TGF-b1) is a potent tumor suppressor but, paradoxically, TGF-b1 enhances tumor growth and metastasis in the late stages of cancer progression. This study investigated the role of TGF-b type I receptor, ALK5, and three mitogen-activated protein kinases (MAPKs) in metastasis by breast cancer cell line MDA-MB-231. We show that autocrine TGF-b signaling in MDA-MB-231 cells is required for tumor cell invasion and tumor angiogenesis. Expression of kinaseinactive ALK5 reduces tumor invasion and formation of new blood vessels within the tumor orthotopic xenografts in severe combined immunodeficiency (SCID) mice. In contrast, constitutively active ALK5-T204D enhances tumor invasion and angiogenesis by stimulating expression of matrix metalloproteinase MMP-9/gelatinase-B. Ablation of MMP-9 in ALK5-T204D cells by RNA interference (RNAi) reduces tumor invasion and tumor growth. Importantly, RNAi-MMP-9 reduces tumor neovasculature and increases tumor cell death. Induction of MMP-9 by TGF-b-ALK5 signaling requires MEK-ERK but not JNK, p38 MAPK or Smad4. Dominant-negative MEK blocks and constitutively active MEK1 enhances MMP-9 expression. However, all three MAPK cascades (ERK, JNK and p38 MAPK) are required for TGF-b-mediated cell migration. Collectively, our results show that TGF-b-ALK5-MAPK signaling in tumor cells promotes tumor angiogenesis and MMP-9 is an important component of this program.

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MAP kinases and cell migration

Cited by 986 publications

References 132 publications

β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt–dependent matrix metalloproteinase-9 expression

ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells

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