scholarly journals α5β1 Integrin Controls Cyclin D1 Expression by Sustaining Mitogen-activated Protein Kinase Activity in Growth Factor-treated Cells

1999 ◽  
Vol 10 (10) ◽  
pp. 3197-3204 ◽  
Author(s):  
Kristin Roovers ◽  
Gabriela Davey ◽  
Xiaoyun Zhu ◽  
Maria Elena Bottazzi ◽  
Richard K. Assoian
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cyclin D1 ◽  
Cell Attachment ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Protein Kinase Activity ◽  
Conditional Expression ◽  
Erk Activity ◽  
Α5β1 Integrin

Cyclin D1 expression is jointly regulated by growth factors and cell adhesion to the extracellular matrix in many cell types. Growth factors are thought to regulate cyclin D1 expression because they stimulate sustained extracellular signal-regulated kinase (ERK) activity. However, we show here that growth factors induce transient ERK activity when added to suspended fibroblasts and sustained ERK activity only when added to adherent fibroblasts. Cell attachment to fibronectin or anti-α5β1 integrin is sufficient to sustain the ERK signal and to induce cyclin D1 in growth factor-treated cells. Moreover, when we force the sustained activation of ERK, by conditional expression of a constitutively active MAP kinase/ERK kinase, we overcome the adhesion requirement for expression of cyclin D1. Thus, at least in part, fibroblasts are mitogen and anchorage dependent, because integrin action allows for a sustained ERK signal and the expression of cyclin D1 in growth factor-treated cells.

scholarly journals A Novel Mitogen-Activated Protein Kinase Is Responsive to Raf and Mediates Growth Factor Specificity

2001 ◽  
Vol 21 (6) ◽  
pp. 2235-2247 ◽  
Author(s):  
Mark Janulis ◽  
Nicholas Trakul ◽  
Geoffrey Greene ◽  
Erik M. Schaefer ◽  
J. D. Lee ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Factor Specificity ◽  
Nih 3T3

ABSTRACT The proto-oncogene Raf is a major regulator of growth and differentiation. Previous studies from a number of laboratories indicate that Raf activates a signaling pathway that is independent of the classic MEK1,2-ERK1,2 cascade. However, no other signaling cascade downstream of Raf has been identified. We describe a new member of the mitogen-activated protein kinase family, p97, an ERK5-related kinase that is activated and Raf associated when cells are stimulated by Raf. Furthermore, p97 is selectively responsive to different growth factors, providing a mechanism for specificity in cellular signaling. Thus, p97 is activated by the neurogenic factor fibroblast growth factor (FGF) but not the mitogenic factor epidermal growth factor (EGF) in neuronal cells. Conversely, the related kinase ERK5 is activated by EGF but not FGF. p97 phosphorylates transcription factors such as Elk-1 and Ets-2 but not MEF2C at transactivating sites, whereas ERK5 phosphorylates MEF2C but not Elk-1 or Ets-2. Finally, p97 is expressed in a number of cell types including primary neural and NIH 3T3 cells. Taken together, these results identify a new signaling pathway that is distinct from the classic Raf-MEK1,2-ERK1,2 kinase cascade and can be selectively stimulated by growth factors that produce discrete biological outcomes.

scholarly journals Integrin αvβ3 Requirement for Sustained Mitogen-activated Protein Kinase Activity during Angiogenesis

1998 ◽  
Vol 140 (5) ◽  
pp. 1255-1263 ◽  
Author(s):  
Brian P. Eliceiri ◽  
Richard Klemke ◽  
Staffan Strömblad ◽  
David A. Cheresh
Keyword(s):  
Endothelial Cells ◽  
Growth Factors ◽  
Growth Factor ◽  
Map Kinase ◽  
Blood Vessels ◽  
Integrin Αvβ3 ◽  
Protein Kinase Activity ◽  
Mitogen Activated Protein ◽  
Erk Activity

Angiogenesis depends on growth factors and vascular cell adhesion events. Integrins and growth factors are capable of activating the ras/MAP kinase pathway in vitro, yet how these signals influence endothelial cells during angiogenesis is unknown. Upon initiation of angiogenesis with basic fibroblast growth factor (bFGF) on the chick chorioallantoic membrane (CAM), endothelial cell mitogen-activated protein (MAP) kinase (ERK) activity was detected as early as 5 min yet was sustained for at least 20 h. The initial wave of ERK activity (5–120 min) was refractory to integrin antagonists, whereas the sustained activity (4–20 h) depended on integrin αvβ3, but not β1 integrins. Inhibition of MAP kinase kinase (MEK) during this sustained αvβ3-dependent ERK signal blocked the formation of new blood vessels while not influencing preexisting blood vessels on the CAM. Inhibition of MEK also blocked growth factor induced migration but not adhesion of endothelial cells in vitro. Therefore, angiogenesis depends on sustained ERK activity regulated by the ligation state of both a growth factor receptor and integrin αvβ3.

scholarly journals Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by β3 integrin

2003 ◽  
Vol 162 (3) ◽  
pp. 499-509 ◽  
Author(s):  
Roberta Faccio ◽  
Deborah V. Novack ◽  
Alberta Zallone ◽  
F. Patrick Ross ◽  
Steven L. Teitelbaum
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Attachment ◽  
Cytoplasmic Tail ◽  
Cytoplasmic Domain ◽  
Small Gtpases ◽  
Cytoskeletal Reorganization ◽  
Integrin Activation ◽  
Intracellular Signals ◽  
Β3 Integrin

The β3 integrin cytoplasmic domain, and specifically S752, is critical for integrin localization and osteoclast (OC) function. Because growth factors such as macrophage colony–stimulating factor and hepatocyte growth factor affect integrin activation and function via inside-out signaling, a process requiring the β integrin cytoplasmic tail, we examined the effect of these growth factors on OC precursors. To this end, we retrovirally expressed various β3 integrins with cytoplasmic tail mutations in β3-deficient OC precursors. We find that S752 in the β3 cytoplasmic tail is required for growth factor–induced integrin activation, cytoskeletal reorganization, and membrane protrusion, thereby affecting OC adhesion, migration, and bone resorption. The small GTPases Rho and Rac mediate cytoskeletal reorganization, and activation of each is defective in OC precursors lacking a functional β3 subunit. Activation of the upstream mediators c-Src and c-Cbl is also dependent on β3. Interestingly, although the FAK-related kinase Pyk2 interacts with c-Src and c-Cbl, its activation is not disrupted in the absence of functional β3. Instead, its activation is dependent upon intracellular calcium, and on the β2 integrin. Thus, the β3 cytoplasmic domain is responsible for activation of specific intracellular signals leading to cytoskeletal reorganization critical for OC function.

scholarly journals Hormonal control of programmed cell death/apoptosis

1998 ◽  
pp. 482-491 ◽  
Author(s):  
W Kiess ◽  
B Gallaher
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Growth Factors ◽  
Growth Factor ◽  
Programmed Cell Death ◽  
Cell Types ◽  
Hormonal Control ◽  
Endocrine Glands ◽  
Survival Factors ◽  
Endocrine Tissues

Apoptosis or programmed cell death is a physiological form of cell death that occurs in embryonic development and during involution of organs. It is characterized by distinct biochemical and morphological changes such as DNA fragmentation, plasma membrane blebbing and cell volume shrinkage. Many hormones, cytokines and growth factors are known to act as general and/or tissue-specific survival factors preventing the onset of apoptosis. In addition, many hormones and growth factors are also capable of inducing or facilitating programmed cell death under physiological or pathological conditions, or both. Steroid hormones are potent regulators of apoptosis in steroid-dependent cell types and tissues such as the mammary gland, the prostate, the ovary and the testis. Growth factors such as epidermal growth factor, nerve growth factor, platelet-derived growth factor (PDGF) and insulin-like growth factor-I act as survival factors and inhibit apoptosis in a number of cell types such as haematopoietic cells, preovulatory follicles, the mammary gland, phaeochromocytoma cells and neurones. Conversely, apoptosis modulates the functioning and the functional integrity of many endocrine glands and of many cells that are capable of synthesizing and secreting hormones. In addition, exaggeration of the primarily natural process of apoptosis has a key role in the pathogenesis of diseases involving endocrine tissues. Most importantly, in autoimmune diseases such as autoimmune thyroid disease and type 1 diabetes mellitus, new data suggest that the immune system itself may not carry the final act of organ injury: rather, the target cells (i.e. thyrocytes and beta cells of the islets) commit suicide through apoptosis. The understanding of how hormones influence programmed cell death and, conversely, of how apoptosis affects endocrine glands, is central to further design strategies to prevent and treat diseases that affect endocrine tissues. This short review summarizes the available evidence showing where and how hormones control apoptosis and where and how programmed cell death exerts modulating effects upon hormonally active tissues.

Differential activation of focal adhesion kinase, Rho and Rac by the ninth and tenth FIII domains of fibronectin

1999 ◽  
Vol 112 (17) ◽  
pp. 2937-2946
Author(s):  
N.A. Hotchin ◽  
A.G. Kidd ◽  
H. Altroff ◽  
H.J. Mardon
Keyword(s):  
Growth Factor ◽  
Focal Adhesion Kinase ◽  
Signaling Pathways ◽  
Focal Adhesion ◽  
Cell Attachment ◽  
Cell Types ◽  
Integrin Receptors ◽  
3T3 Cells ◽  
Swiss 3T3 ◽  
Kinase Phosphorylation

Fibronectins are widely expressed extracellular matrix ligands that are essential for many biological processes. Fibronectin-induced signaling pathways are elicited in diverse cell types when specific integrin receptors bind to the ninth and tenth FIII domains, FIII9-10. Integrin-mediated signal transduction involves activation of signaling pathways of the growth factor-dependent Ras-related small GTP-binding proteins Rho and Rac, and phosphorylation of focal adhesion kinase. We have dissected the requirement of FIII9 and FIII10 for Rho and Rac activity and phosphorylation of focal adhesion kinase in BHK fibroblasts and Swiss 3T3 cells. We demonstrate that FIII10 supports cell attachment but does not induce phosphorylation of focal adhesion kinase. In Swiss 3T3 cells, growth factor-independent phosphorylation of focal adhesion kinase and downstream adhesion events are dependent upon the presence of FIII9 in the intact FIII9-10 pair, whereas FIII10-mediated focal adhesion kinase phosphorylation requires a synergistic signal from growth factors. Furthermore, FIII10 is able to elicit cellular responses mediated by Rho, but not Rac, whereas FIII9-10 can elicit both Rho- and Rac-mediated responses. We propose that activation of specific integrin subunits by the FIII10 and FIII9-10 ligands elicits distinct signaling events. This may represent a general molecular mechanism for activation of receptor-specific signaling pathways by a multi-domain ligand.

scholarly journals IQGAP1 Is a Scaffold for Mitogen-Activated Protein Kinase Signaling

2005 ◽  
Vol 25 (18) ◽  
pp. 7940-7952 ◽  
Author(s):  
Monideepa Roy ◽  
Zhigang Li ◽  
David B. Sacks
Keyword(s):  
Growth Factor ◽  
Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Signaling ◽  
Cellular Functions ◽  
Molecular Scaffold ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Erk Activity

ABSTRACT IQGAP1 modulates many cellular functions such as cell-cell adhesion, transcription, cytoskeletal architecture, and selected signaling pathways. We previously documented that IQGAP1 binds extracellular signal-regulated kinase (ERK) 2 and regulates growth factor-stimulated ERK activity. Here we show that MEK, the molecule immediately upstream of ERK in the Ras/mitogen-activated protein (MAP) kinase signaling cascade, also interacts directly with IQGAP1. Both MEK1 and MEK2 bound IQGAP1 in vitro and coimmunoprecipitated with IQGAP1. The addition of ERK2 enhanced by fourfold the in vitro interaction of MEK2 with IQGAP1 without altering binding of MEK1. Similarly, ERK1 promoted MEK binding to IQGAP1, but either MEK protein altered the association between IQGAP1 and ERK. Epidermal growth factor (EGF) differentially regulated binding, enhancing MEK1 interaction while reducing MEK2 binding to IQGAP1. In addition, both knockdown and overexpression of IQGAP1 reduced EGF-stimulated activation of MEK and ERK. Analyses with selective IQGAP1 mutant constructs indicated that MEK binding is crucial for IQGAP1 to modulate EGF activation of ERK. Our data strongly suggest that IQGAP1 functions as a molecular scaffold in the Ras/MAP kinase pathway.

scholarly journals Mos in the Oocyte: How to Use MAPK Independently of Growth Factors and Transcription to Control Meiotic Divisions

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Aude Dupré ◽  
Olivier Haccard ◽  
Catherine Jessus
Keyword(s):  
Growth Factors ◽  
Transcriptional Activation ◽  
Biological Activities ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Specific Cell ◽  
Cell Type ◽  
Specific Cell Type ◽  
Mitogen Activated Protein

In many cell types, the mitogen-activated protein kinase (MAPK) also named extracellular signal-regulated kinase (ERK) is activated in response to a variety of extracellular growth factor-receptor interactions and leads to the transcriptional activation of immediate early genes, hereby influencing a number of tissue-specific biological activities, as cell proliferation, survival and differentiation. In one specific cell type however, the female germ cell, MAPK does not follow this canonical scheme. In oocytes, MAPK is activated independently of growth factors and tyrosine kinase receptors, acts independently of transcriptional regulation, plays a crucial role in controlling meiotic divisions, and is under the control of a peculiar upstream regulator, the kinase Mos. Mos was originally identified as the transforming gene of Moloney murine sarcoma virus and its cellular homologue was the first proto-oncogene to be molecularly cloned. What could be the specific roles of Mos that render it necessary for meiosis? Which unique functions could explain the evolutionary cost to have selected one gene to only serve for few hours in one very specific cell type? This review discusses the original features of MAPK activation by Mos and the roles of this module in oocytes.

scholarly journals AIB1 Is a Conduit for Kinase-Mediated Growth Factor Signaling to the Estrogen Receptor

2000 ◽  
Vol 20 (14) ◽  
pp. 5041-5047 ◽  
Author(s):  
Jaime Font de Mora ◽  
Myles Brown
Keyword(s):  
Estrogen Receptor ◽  
Growth Factors ◽  
Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Mapk Activation ◽  
Mitogen Activated Protein

ABSTRACT Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1.

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