Wei Li

University of Southern California, Los Angeles, California, United States

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Publications (39)243.83 Total impact

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    ABSTRACT: Recent findings suggest that hypoxia of the tumor microenvironment contributes to immune escape from natural killer (NK) cell-mediated cytotoxicity. Heat shock protein 70 (Hsp70) and the stress-regulated major histocompatibility class I chain-related protein A and B (MICA/B) both serve as ligands for activated NK cells when expressed on the cell surface of tumor cells. Herein, we studied the effects of hypoxia and hypoxia-inducible factor-1α (HIF-1α) on the membrane expression of these NK cell ligands in H1339 with high and MDA-MB-231 tumor cells with low basal HIF-1α levels and its consequences on NK cell-mediated cytotoxicity. We could show that a hypoxia-induced decrease in the membrane expression of MICA/B and Hsp70 on H1339 and MDA-MB-231 cells, respectively, is associated with a reduced sensitivity to NK cell-mediated lysis. A knockdown of HIF-1α revealed that the decreased surface expression of MICA/B under hypoxia is dependent on HIF-1α in H1339 cells with high basal HIF-1α levels. Hypoxia and HIF-1α did not affect the MICA/B expression in MDA-MB-231 cells but reduced the Hsp70 membrane expression which in turn also impaired NK cell recognition. Furthermore, we could show that the hypoxia-induced decrease in membrane Hsp70 is independent of HIF-1α in MDA-MB-231. Our data indicate that hypoxia-induced downregulation of both NK cell ligands MICA/B and Hsp70 impairs NK cell-mediated cytotoxicity, whereby only MICA/B appears to be regulated by HIF-1α.
    Cell Stress and Chaperones 08/2014; · 2.48 Impact Factor
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    ABSTRACT: Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the mechanistic properties of a specific group of NIR heptamethine carbocyanines including MHI-148 dye we identified and synthesized, and demonstrated these dyes to achieve cancer-specific imaging and targeting via a hypoxia-mediated mechanism. We found that cancer cells and tumor xenografts exhibited hypoxia-dependent MHI-148 dye uptake in vitro and in vivo, which was directly mediated by hypoxia-inducible factor 1α (HIF1α). Microarray analysis and dye uptake assay further revealed a group of hypoxia-inducible organic anion-transporting polypeptides (OATPs) responsible for dye uptake, and the correlation between OATPs and HIF1α was manifested in progressive clinical cancer specimens. Finally, we demonstrated increased uptake of MHI-148 dye in situ in perfused clinical tumor samples with activated HIF1α/OATPs signaling. Our results establish these NIRF dyes as potential tumor hypoxia-dependent cancer-targeting agents and provide a mechanistic rationale for continued development of NIRF imaging agents for improved cancer detection, prognosis and therapy.
    Biomaterials 06/2014; · 8.31 Impact Factor
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    ABSTRACT: Chronic and non-healing skin wounds represent a significant clinical, economic and social problem worldwide. Currently, there are few effective treatments. Lack of well-defined animal models to investigate wound healing mechanisms and furthermore to identify new and more effective therapeutic agents still remains a major challenge. Pig skin wound healing is close to humans. However, standardized pig wound healing models with demonstrated validity for testing new wound healing candidates are unavailable. Here we report a systematic evaluation and establishment of both acute and diabetic wound healing models in pigs, including wound-creating pattern for drug treatment versus control, measurements of diabetic parameters and the time for detecting delayed wound healing. We find that treatment and control wounds should be on the opposite and corresponding sides of a pig. We demonstrate a strong correlation between duration of diabetic conditions and the length of delay in wound closure. Using these new models, we narrow down the minimum therapeutic entity of secreted Hsp90α to a 27-amino acid peptide, called fragment-8 (F-8). In addition, results of histochemistry and immunohistochemistry analyses reveal more organized epidermis and dermis in Hsp90α-healed wounds than the control. Finally, Hsp90α uses a similar signaling mechanism to promote migration of isolated pig and human keratinocytes and dermal fibroblasts. This is the first report that shows standardized pig models for acute and diabetic wound healing studies and proves its usefulness with both an approved drug and a new therapeutic agent.
    PLoS ONE 01/2014; 9(12):e113956. · 3.53 Impact Factor
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    ABSTRACT: Normal cells secrete heat shock protein-90alpha (Hsp90α) in response to tissue injury. Tumor cells have managed to constitutively secrete Hsp90α during invasion and metastasis. The sole function of the extracellular Hsp90α (eHsp90α) is to promote cell motility, a critical event for both wound healing and tumor progression. The mechanism of the pro-motility action by eHsp90α, however, remained elusive. A key issue is whether eHsp90α still acts as a chaperone outside the cells or it is a new and bona fide signaling molecule. Here, we provide evidence that eHsp90α utilizes a unique trans-membrane signaling mechanism to promote cell motility and wound healing. First, the subdomain II in the extracellular part of the low-density lipoprotein receptor-related protein-1 (LRP-1) receives eHsp90α signal. Then, the NPVY, but not the NPTY, motif in the cytoplamic tail of LRP-1 connects eHsp90α signaling to serine-473, but not threonine-308, phosphorylation in Akt kinases. Individual knockdown of Akt1, Akt2 or Akt3 revealed the importance of Akt1 and Ak2 in eHsp90α-induced cell motility. Akt gene rescue experiments suggest that Akt1 and Akt2 work in concert, rather than independently, to mediate the eHsp90α pro-motility signaling. Finally, Akt1- and Akt2- knockout mice showed impaired wound healing that cannot be corrected by topical application with eHsp90α protein.
    Molecular and Cellular Biology 10/2013; · 5.04 Impact Factor
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    ABSTRACT: Mitochondrial abnormalities are associated with cancer development, yet how oncogenic signals affect mitochondrial functions has not been fully understood. In this study, we investigate the relationship between mitochondrial alterations and PI3K/protein kinase B (AKT) signaling activation using hepatocytes and liver tissues as our experimental models. We show here that liver-specific deletion of Pten, which leads to activation of PI3K/AKT, is associated with elevated oxidative stress, increased mitochondrial mass and augmented respiration accompanied by enhanced glycolysis. Consistent with these observations, estrogen-related receptor α (ERRα), an orphan nuclear receptor known for its role in mitochondrial biogenesis, is up-regulated in the absence of PTEN. Our pharmacological and genetic studies show that PI3K/AKT activity regulates the expression of ERRα and mitochondrial biogenesis/respiration. Further, cAMP response element-binding protein (CREB), as a downstream target of AKT play a role in the regulation of ERRα, independent of PKA signaling. ERRα regulates reactive oxygen species (ROS) production and ERRα knockdown attenuates proliferation and colony forming potential in Pten-null hepatocytes. Finally, analysis of clinical datasets from liver tissues showed a negative correlation between expressions of ERRα and PTEN in liver cancer patients. Therefore, this study has established a previously unrecognized link between a growth signal and mitochondrial metabolism.
    Journal of Biological Chemistry 07/2013; · 4.65 Impact Factor
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    ABSTRACT: Despite extensive investigative studies and clinical trials over the past two decades, we still do not understand why cancer cells are more sensitive to the cellular toxicity of Hsp90 inhibitors than normal cells. We still do not understand why only some cancer cells are sensitive to the Hsp90 inhibitors. Based on studies of the past few years, we argue that the selected sensitivity of cancer cells to Hsp90 inhibitors, such as 17-N-allylamino-17-demethoxygeldanamycin, is due to inhibition of the extracellular Hsp90 (eHsp90) rather than intracellular Hsp90 by these inhibitors. Because not all tumor cells utilize eHsp90 for motility, invasion and metastasis, only the group of "eHsp90-dependent" cancer cells is sensitive to Hsp90 inhibitors. If these notions prove to be true, pharmaceutical agents that selectively target eHsp90 should be more effective on tumor cells and less toxic on normal cells than current inhibitors that nondiscriminatively target both extracellular and intracellular Hsp90.
    International review of cell and molecular biology 01/2013; 303:203-35. · 4.97 Impact Factor
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    ABSTRACT: When skin is wounded, migration of epidermal keratinocytes at the wound edge initiates within hours, whereas migration of dermal fibroblasts toward the wounded area remains undetectable until several days later. This "cell type traffic" regulation ensures proper healing of the wound, as disruptions of the regulation could either cause delay of wound healing or result in hypertrophic scars. TGFβ3 is the critical traffic controller that selectively halts migration of the dermal, but not epidermal, cells to ensure completion of wound re-epithelialization prior to wound remodeling. However, the mechanism of TGFβ3's anti-motility signaling has never been investigated. We report here that activated TβRII transmits the anti-motility signal of TGFβ3 in full to TβRI, since expression of the constitutively activated TβRI-TD mutant was sufficient to replace TGFβ3 to block PDGF-bb-induced dermal fibroblast migration. Second, the three components of R-Smad complex are all required. Individual downregulation of Smad2, Smad3 or Smad4 prevented TGFβ3 from inhibiting dermal fibroblast migration. Third, Protein Kinase Array allowed us to identify the protein kinase A (PKA) as a specific downstream effector of R-Smads in dermal fibroblasts. Activation of PKA alone blocked PDGF-bb-induced dermal fibroblast migration, just like TGFβ3. Downregulation of PKA's catalytic subunit nullified the anti-motility signaling of TGFβ3. This is the first report on anti-motility signaling mechanism by TGFβ family cytokines. Significance of this finding is not only limited to wound healing but also to other human disorders, such as heart attack and cancer, where the diseased cells have often managed to avoid the anti-motility effect of TGFβ.
    Biology open. 12/2012; 1(12):1169-77.
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    ABSTRACT: Self-prepared styrene–isoprene–butadiene rubber (SIBR) was anionically synthesised and modified by a hydrogenation reaction. The hydrogenated SIBR (HSIBR) was used as a viscosity index improver in lubricants due to its improved thermal and oxidative resistance. The precursors and corresponding hydrogenated polymers were characterised by size-exclusion chromatography, Fourier transform infrared, proton nuclear magnetic resonance (1H-NMR) spectroscopy, differential scanning calorimetry and thermal gravimetric analysis. Moreover, the efficiencies of HSIBR as viscosity index improvers for SAE 5W-30 multigrade oils (150N HG base oil) were studied. The results confirm that adding 1 wt.% of HSIBR markedly increases the specific viscosity of base oil, increases the viscosity index (119 for base oil) up to a value between 158 and 164 and maintains the shear stability well. Furthermore, the HSIBR-containing oil possesses a high high-temperature and high-shear viscosity without destroying its low-temperature fluidity. Copyright © 2012 John Wiley & Sons, Ltd.
    Lubrication Science 06/2012; 24(4). · 0.68 Impact Factor
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    ABSTRACT: Time-resolved synchrotron small angle X-ray scattering (SAXS) was used to investigate the early stages of crystallization in melt crystallized polyethylene. Classic Gibbs nucleation or density fluctuation theory can be used to describe the primary nucleation mechanism. At 110 °C, no signal of crystallization can be detected by SAXS for 30 min. When it is lower than 110 °C, the low q scattering intensity (0.008 < q < 0.03 Å−1) begins to upturn, and the primary nucleation process starts. The measured fractal dimension of the critical nuclei is in the vicinity of 3 which is close to the prediction of classic Gibbs nucleation theory. The growth rate of density fluctuations R(q) at different scattering vector q for different temperatures was obtained by analyzing the increase of scattering intensities. The results show that the growth rate of density fluctuation gets much bigger with the decrease of the isothermal crystallization temperature, but there is no signal of spinodal decomposition mechanism, in which there should be a linear relationship between R(q)/q2 and q2.
    Polymer 05/2012; 53(12):2315–2319. · 3.77 Impact Factor
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    ABSTRACT: Extracellular Hsp90 proteins, including "membrane-bound", "released" and "secreted", were first reported more than two decades ago. Only studies of the past 7years have begun to reveal a picture for when, how and why Hsp90 gets exported by both normal and tumor cells. Normal cells secrete Hsp90 in response to tissue injury. Tumor cells have managed to constitutively secrete Hsp90 for tissue invasion. In either case, sufficient supply of the extracellular Hsp90 can be guaranteed by its unusually abundant storage inside the cells. A well-characterized function of secreted Hsp90α is to promote cell motility, a crucial event for both wound healing and cancer. The reported targets for extracellular Hsp90α include MMP2, LRP-1, tyrosine kinase receptors and possibly more. The pro-motility activity of secreted Hsp90α resides within a fragment, called 'F-5', at the boundary between linker region and middle domain. Inhibition of its secretion, neutralization of its extracellular action or interruption of its signaling through LRP-1 block wound healing and tumor invasion in vitro and in vivo. In normal tissue, topical application of F-5 promotes acute and diabetic wound healing far more effectively than US FDA-approved conventional growth factor therapy in mice. In cancer, drugs that selectively target the F-5 region of secreted Hsp90 by cancer cells may be more effective and less toxic than those that target the ATPase of the intracellular Hsp90. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).
    Biochimica et Biophysica Acta 03/2012; 1823(3):730-41. · 4.66 Impact Factor
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    ABSTRACT: Ionizing irradiation is a commonly accepted treatment modality for lung cancer patients. However, the clinical outcome is hampered by normal tissue toxicity and tumor hypoxia. Since tumors often have higher levels of active heat shock protein 90 (Hsp90) than normal tissues, targeting of Hsp90 might provide a promising strategy to sensitize tumors towards irradiation. Hsp90 client proteins include oncogenic signaling proteins, cell cycle activators, growth factor receptors and hypoxia inducible factor-1α (HIF-1α). Overexpression of HIF-1α is assumed to promote malignant transformation and tumor progression and thus might reduce the accessibility to radiotherapy. Herein, we describe the effects of the novel Hsp90 inhibitor NVP-AUY922 and 17-allylamino-17-demethoxygeldanamycin (17-AAG), as a control, on HIF-1α levels and radiosensitivity of lung carcinoma cells under normoxic and hypoxic conditions. NVP-AUY922 exhibited a similar biological activity to that of 17-AAG, but at only 1/10 of the dose. As expected, both inhibitors reduced basal and hypoxia-induced HIF-1α levels in EPLC-272H lung carcinoma cells. However, despite a down-regulation of HIF-1α upon Hsp90 inhibition, sensitivity towards irradiation remained unaltered in EPLC-272H cells under normoxic and hypoxic conditions. In contrast, treatment of H1339 lung carcinoma cells with NVP-AUY922 and 17-AAG resulted in a significant up-regulation of their initially high HIF-1α levels and a concomitant increase in radiosensitivity. In summary, our data show a HIF-1α-independent radiosensitization of normoxic and hypoxic H1339 lung cancer cells by Hsp90 inhibition.
    PLoS ONE 01/2012; 7(2):e31110. · 3.53 Impact Factor
  • Cellular Trafficking of Cell Stress Proteins in Health and Disease, 1 edited by Brian Henderson, A Graham Pockley, 01/2012: chapter Heat Shock Protein 90 Versus Conventional Growth Factors in Acute and Diabetic Wound Healing: pages 259-277; Springer., ISBN: 978-94-007-4739-5
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    ABSTRACT: Deregulated accumulation of hypoxia-inducible factor-1α (HIF-1α) is a hallmark of many solid tumors. Directly targeting HIF-1α for therapeutics is challenging. Our finding that HIF-1α regulates secretion of heat shock protein-90α (Hsp90α) for cell migration raises the exciting possibility that targeting the secreted Hsp90α from HIF-1α-positive tumors has a better clinical outlook. Using the HIF-1α-positive and metastatic breast cancer cells MDA-MB-231, we show that down-regulation of the deregulated HIF-1α blocks Hsp90α secretion and invasion of the cells. Reintroducing an active, but not an inactive, HIF-1α into endogenous HIF-1α-depleted cells rescues both Hsp90α secretion and invasion. Inhibition of Hsp90α secretion, neutralization of secreted Hsp90α action, or removal of the cell surface LRP-1 receptor for secreted Hsp90α reduces the tumor cell invasion in vitro and lung colonization and tumor formation in nude mice. Furthermore, we localized the tumor-promoting effect to a 115-amino acid region in secreted Hsp90α called F-5. Supplementation with F-5 is sufficient to bypass the blockade of HIF-1α depletion and resumes invasion by the tumor cells under serum-free conditions. Because normal cells do not secrete Hsp90α in the absence of stress, drugs that target F-5 should be more effective and less toxic in treatment of HIF-1α-positive tumors in humans.
    Molecular biology of the cell 12/2011; 23(4):602-13. · 5.98 Impact Factor
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    ABSTRACT: Wounds that fail to heal in a timely manner, for example, diabetic foot ulcers, pose a health, economic, and social problem worldwide. For decades, conventional wisdom has pointed to growth factors as the main driving force of wound healing; thus, growth factors have become the center of therapeutic developments. To date, becaplermin (recombinant human PDGF-BB) is the only US FDA-approved growth factor therapy, and it shows modest efficacy, is costly, and has the potential to cause cancer in patients. Other molecules that drive wound healing have therefore been sought. In this context, it has been noticed that wounds do not heal without the participation of secreted Hsp90α. Here, we report that a 115-aa fragment of secreted Hsp90α (F-5) acts as an unconventional wound healing agent in mice. Topical application of F-5 peptide promoted acute and diabetic wound closure in mice far more effectively than did PDGF-BB. The stronger effect of F-5 was due to 3 properties not held by conventional growth factors: its ability to recruit both epidermal and dermal cells; the fact that its ability to promote dermal cell migration was not inhibited by TGF-β; and its ability to override the inhibitory effects of hyperglycemia on cell migration in diabetes. The discovery of F-5 challenges the long-standing paradigm of wound healing factors and reveals a potentially more effective and safer agent for healing acute and diabetic wounds.
    The Journal of clinical investigation 11/2011; 121(11):4348-61. · 15.39 Impact Factor
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    ABSTRACT: TGFβ binding to the TGFβ receptor (TβR) activates R-Smad-dependent pathways, such as Smad2/3, and R-Smad-independent pathways, such as ERK1/2. The mechanism of the TGFβ-TβRII-TβRI-Smad2/3 pathway is established; however, it is not known how TGFβ activates ERK1/2. We show here that although TGFβ equally activated Smad2/3 in all cells, it selectively activated ERK1/2 in dermal cells and inhibited ERK1/2 in epidermal cells. These opposite effects correlated with the distinct expression levels of TβRII, which are 7- to 18-fold higher in dermal cells than in epidermal cells. Reduction of TβRII expression in dermal cells abolished TGFβ-stimulated ERK1/2 activation. Upregulation of TβRII expression in epidermal cells to a similar level as that in dermal cells switched TGFβ-induced ERK1/2 inhibition to ERK1/2 activation. More intriguingly, in contrast to the equal importance of TβRII in mediating TGFβ signaling to both Smad2/3 and ERK1/2, knockdown of TβRI/Alk5 blocked activation of only Smad2/3, not ERK1/2, in dermal cells. Similarly, expression of the constitutively activated TβRI-TD kinase activated only Smad2/3 and not ERK1/2 in epidermal cells. This study provides an explanation for why TGFβ selectively activates ERK1/2 in certain cell types and direct evidence for TβRI-independent TβRII signaling to a R-Smad-independent pathway.
    Journal of Cell Science 01/2011; 124(Pt 1):19-24. · 5.88 Impact Factor
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    The EMBO Journal 01/2011; 30(24):5022. · 9.82 Impact Factor
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    ABSTRACT: Until recently, heat shock protein 90 (Hsp90) has been mostly known as an abundant intracellular chaperone with more than 100 target proteins often involved in control of cell metabolism, survival, growth and differentiation. Hsp90 has been a target for anti-cancer drugs, since it was found either overexpressed or overactive in cancer cells. For more than a decade, geldanamycin (GM)-derived inhibitors of Hsp90's ATPase have entered various clinical trials around the world. Despite of high expectations, the efficacy of these inhibitors in humans has been less than what was hoped for. While newer generations of GM inhibitors are being developed and tested in several ongoing clinical trials, recent studies have discovered a surprising need for cancer cells to constitutively secrete Hsp90α for invasion and metastasis. A main function for secreted Hsp90 is to promote cell motility via the cell surface receptor LRP1 and/or secreted MMP2. Distinct from its intracellular chaperone function that requires the N-terminal ATPase and the C-terminal dimerization, the pro-motility activity of extracellular Hsp90α resides in a highly charged peptide between the linker region and the middle domain in Hsp90α. Selective inhibition of secreted Hsp90α blocks tumor cell invasion in vitro and in vivo. More importantly, since Hsp90α secretion does not occur in normal cells under physiological conditions, drugs that selectively target the secreted Hsp90α at its pro-motility region may prove to be more effective and less toxic for treatment of cancer patients.
    Current Signal Transduction Therapy 04/2010; 5(2):121-127. · 0.45 Impact Factor
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    ABSTRACT: Hypoxia is a microenvironmental stress in many pathological conditions, including wound healing and tumor invasion. Under hypoxia, the cells are forced to adapt alternative and self-supporting mechanisms. Understanding these mechanisms may lead to new insights into human disorders. We report here a novel autocrine signaling mechanism by which hypoxia promotes human keratinocyte (HK) migration. First, hypoxia triggers HKs to secrete heat shock protein 90-alpha (HSP90alpha) via a HIF1-dependent pathway. The secreted HSP90alpha in turn promotes migration, but not proliferation, of the cells. Disruption of the secretion or extracellular function of HSP90alpha blocked hypoxia-stimulated HK migration. The ubiquitously expressed surface receptor, LRP1 (LDL-receptor-related protein 1), mediates the HSP90alpha signaling. Inhibition of LRP1 binding to extracellular HSP90alpha by neutralizing antibodies or genetic silencing of the LRP1 receptor by RNAi completely nullified hypoxia-driven HK migration. Finally, re-introducing a RNAi-resistant LRP1 cDNA into LRP1-downregulated HKs rescued the motogenic response of the cells to hypoxia. We propose that the hypoxia-HSP90alpha-LRP1 autocrine loop provides previously unrecognized therapeutic targets for human disorders such as chronic wounds and cancer invasion.
    Journal of Cell Science 05/2009; 122(Pt 10):1495-8. · 5.88 Impact Factor
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    ABSTRACT: Expressed in embryonic development, matrix metalloprotein-9 (MMP-9) is absent in most of developed adult tissues, but recurs in inflammation during tissue injury, wound healing, tumor formation and metastasis. Expression of MMP-9 is tightly controlled by extracellular cues including pro-inflammatory cytokines and extracellular matrix (ECM). While the pathologic functions of MMP-9 are evident, the intracellular signaling pathways to control its expression are not fully understood. In this study we investigated mechanism of cytokine induced MMP-9 with particular emphasis on the role of p21-activated-kinase-1 (PAK1) and the down stream signaling. In response to TNF-alpha or IL-1alpha, PAK1 was promptly activated, as characterized by a sequential phosphorylation, initiated at threonine-212 followed by at threonine-423 in the activation loop of the kinase, in human skin keratinocytes, dermal fibroblasts, and rat hepatic stellate cells. Ectopic expression of PAK1 variants, but not p38 MAP kinase, impaired the TNF-alpha-induced MMP-9 expression, while other MMPs such as MMP-2, -3 and -14 were not affected. Activation of Jun N-terminal kinase (JNK) and NF-kappaB has been demonstrated to be essential for MMP-9 expression. Expression of inactive PAK1 variants impaired JNK but not NF-kappaB activation, which consequently suppressed the 5'-promoter activities of the MMP-9 gene. After the cytokine-induced phosphorylation, both ectopically expressed and endogenous PAK1 proteins were promptly accumulated even in the condition of suppressing protein synthesis, suggesting the PAK1 protein is stabilized upon TNF-alpha stimulation. Stabilization of PAK1 protein by TNF-alpha treatment is independent of the kinase catalytic activity and p21 GTPase binding capacities. In contrast to epithelial cells, mesenchymal cells require 3-dimensional type-I collagen in response to TNF-alpha to massively express MMP-9. The collagen effect is mediated, in part, by boost JNK activation in a way to cooperate the cytokine signaling. We identified a novel mechanism for MMP-9 expression in response to injury signals, which is mediated by PAK1 activation and stabilization leading JNK activation.
    BMC Immunology 04/2009; 10:15. · 2.61 Impact Factor
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    ABSTRACT: Platelet-derived growth factor BB (PDGF-BB) is a Food and Drug Administration (FDA)-approved growth factor, acting as a mitogen and motogen of dermal fibroblasts (DFs), for skin wound healing. The two closely related SH2/SH3 adapter proteins, Nckalpha and Nckbeta, connect PDGF-BB signaling to the actin cytoskeleton and cell motility. The mechanism has not been fully understood. In this study, we investigated, side by side, the roles of Nckalpha and Nckbeta in PDGF-BB-stimulated DF migration. We found that cells expressing the PDGFRbeta-Y751F mutant (preventing Nckalpha binding) or PDGFRbeta-Y1009F mutant (preventing Nckbeta binding), DF cells isolated from Nckalpha- or Nckbeta-knockout mice, and primary human DF cells with RNA interference (RNAi) knockdown of the endogenous Nckalpha or Nckbeta all failed to migrate in response to PDGF-BB. Overexpression of the middle SH3 domain of Nckalpha or Nckbeta alone in human DFs also blocked PDGF-BB-induced cell migration. However, neither Nckalpha nor Nckbeta was required for the activation of the PDGF receptor, p21-activated protein kinase (Pak1), AKT, extracellular signal-regulated kinase (ERK) 1/2, or p38MAP by PDGF-BB. Although PDGF-BB stimulated the membrane translocation of both Nckalpha and Nckbeta, Nckalpha appeared to mediate Cdc42 signaling for filopodium formation, whereas Nckbeta mediated Rho signaling to induce stress fibers. Thus, this study has elucidated the independent roles and mechanisms of action of Nckalpha and Nckbeta in DF migration, which is critical for wound healing.
    Journal of Investigative Dermatology 03/2009; 129(8):1909-20. · 6.19 Impact Factor

Publication Stats

736 Citations
243.83 Total Impact Points

Institutions

  • 2002–2014
    • University of Southern California
      • • Department of Dermatology
      • • Norris Comprehensive Cancer Center
      • • Keck School of Medicine
      • • Department of Medicine
      • • Department of Surgery
      Los Angeles, California, United States
  • 2013
    • Keck School of Medicine USC
      Los Angeles, California, United States
  • 2012
    • Dalian University of Technology
      • School of Chemical Engineering
      Lü-ta-shih, Liaoning, China
  • 2004–2011
    • University of California, Los Angeles
      • • Division of Dermatology
      • • Department of Medicine
      Los Angeles, CA, United States
  • 2007
    • VA Greater Los Angeles Healthcare System
      Los Angeles, California, United States