Transforming Growth Factor β Activation of p44mapk in Proliferating Cultures of Epithelial Cells

Hartsough, Melanie T.; Mulder, Kathleen M.

doi:10.1074/jbc.270.13.7117

Cited by 299 publications

(204 citation statements)

References 64 publications

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“…In the breast cancer MDA-MB-231 cell line, TGF-b1 activates both Smad2/ 3 and Smad1/5 signaling suggesting that both ALK1 and ALK5 may operate in these cells . TGF-b-mediated activation of MAPKs may involve TGF-b-activated kinase 1 (TAK1) (Yamaguchi et al, 1995;Shibuya et al, 1996) or small GTPases (Hartsough and Mulder, 1995;Mucsi et al, 1996;Frey and Mulder, 1997;Adachi-Yamada et al, 1999;Engel et al, 1999;Bakin et al, 2002). Activation of PI3K-Akt signaling by TGF-b receptors (Bakin et al, 2000; requires small Rho-like GTPases (Bakin et al, 2000).…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

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

2006

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“…The Smad complex binds to DNA directly or indirectly via interaction with other proteins, recruiting coactivators to mediate the transcription of genes involved in a variety of pathways (28). In addition, TGF-b1 signals through a variety of diverse, Smad-independent pathways that modulate [Ca 21 ] i levels (29,30), ras homolog gene family, member A (RhoA)/rho-associated protein kinase (ROCK) (31), MAPK, and ERK pathways (32,33). Both Smad-independent and Smad-dependent pathways may mediate airway remodeling and AHR.…”

Section: Tgf-b1 Signalingmentioning

confidence: 99%

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

Ojiaku

Yoo

Panettieri

2017

Am J Respir Cell Mol Biol

106

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The pathogenesis of asthma includes a complex interplay among airway inflammation, hyperresponsiveness, and remodeling. Current evidence suggests that airway structural cells, including bronchial smooth muscle cells, myofibroblasts, fibroblasts, and epithelial cells, mediate all three aspects of asthma pathogenesis. Although studies show a connection between airway remodeling and changes in bronchomotor tone, the relationship between the two remains unclear. Transforming growth factor b1 (TGF-b1), a growth factor elevated in the airway of patients with asthma, plays a role in airway remodeling and in the shortening of various airway structural cells. However, the role of TGF-b1 in mediating airway hyperresponsiveness remains unclear. In this review, we summarize the literature addressing the role of TGF-b1 in airway remodeling and shortening. Through our review, we aim to further elucidate the role of TGF-b1 in asthma pathogenesis and the link between airway remodeling and airway hyperresponsiveness in asthma and to define TGF-b1 as a potential therapeutic target for reducing asthma morbidity and mortality.

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“…The TGF␤ responsiveness of cells was verified by [ 3 H]thymidine incorporation assays, performed as described previously (Hartsough and Mulder, 1995). For Figure 5, pools of Mv1Lu cells stably transfected with km23-FLAG or EV were plated at 2 ϫ 10 3 cells per 96-well dish and were analyzed at several days thereafter using crystal violet (EMScience #1011; Fisher Scientific, Pittsburgh, PA), according to the assay protocol at http://www-ufk.med.uni-rostock.de/lablinks/protocols/e_protocols/cvassay.htm.…”

Section: Growth Assaysmentioning

confidence: 99%

“…The Smad family of signaling intermediates plays an important role in mediating TGF␤ responses (Attisano and Wrana, 2000;ten Dijke et al, 2000;Yue and Mulder, 2001). Moreover, TGF␤ has been shown to regulate Ras (Mulder and Morris, 1992;Hartsough et al, 1996;Yue et al, 1998) and several components of the mitogen-activated protein kinase (Mapk) pathways (Hartsough and Mulder, 1995;Frey and Mulder, 1997;Mulder, 2000;Sporn and Vilcek, 2000;Yue and Mulder, 2001). In addition to the Ras/Mapk and Smad pathways, several proteins have been identified based upon their interaction with the TGF␤ receptors (Yue and Mulder, 2001).…”

Section: Introductionmentioning

confidence: 99%

A Novel Transforming Growth Factor-β Receptor-interacting Protein That Is Also a Light Chain of the Motor Protein Dynein

Tang¹,

Staub²,

Gao

et al. 2002

MBoC

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The phosphorylated, activated cytoplasmic domains of the transforming growth factor-␤ (TGF␤) receptors were used as probes to screen an expression library that was prepared from a highly TGF␤-responsive intestinal epithelial cell line. One of the TGF␤ receptor-interacting proteins isolated was identified to be the mammalian homologue of the LC7 family (mLC7) of dynein light chains (DLCs). This 11-kDa cytoplasmic protein interacts with the TGF␤ receptor complex intracellularly and is phosphorylated on serine residues after ligand-receptor engagement. Forced expression of mLC7-1 induces specific TGF␤ responses, including an activation of Jun N-terminal kinase (JNK), a phosphorylation of c-Jun, and an inhibition of cell growth. Furthermore, TGF␤ induces the recruitment of mLC7-1 to the intermediate chain of dynein. A kinase-deficient form of TGF␤ RII prevents both mLC7-1 phosphorylation and interaction with the dynein intermediate chain (DIC). This is the first demonstration of a link between cytoplasmic dynein and a natural growth inhibitory cytokine. Furthermore, our results suggest that TGF␤ pathway components may use a motor protein light chain as a receptor for the recruitment and transport of specific cargo along microtublules. INTRODUCTIONTransforming growth factor-␤ (TGF␤) is the prototype for the TGF␤ superfamily of highly conserved growth regulatory polypeptides that also includes the activins, inhibins, bone morphogenetic proteins, decapentaplegic (Dpp), nodal, Lefty, and others (Roberts, 1998;Sporn and Vilcek, 2000;Yue and Mulder, 2001). Alterations in the TGF␤ signaling components and pathways have been implicated in a vast array of human pathologies, including cancer (Massague et al., 2000;Sporn and Vilcek, 2000;Derynck et al., 2001).TGF␤ binds to two types of transmembrane serine/threonine kinase receptors (RI and RII) in a heterotetrameric complex, to activate downstream components (Roberts, 1998; Massague et al., 2000;Sporn and Vilcek, 2000;Yue and Mulder, 2001). The Smad family of signaling intermediates plays an important role in mediating TGF␤ responses (Attisano and Wrana, 2000;ten Dijke et al., 2000;Yue and Mulder, 2001). Moreover, TGF␤ has been shown to regulate Ras (Mulder and Morris, 1992;Hartsough et al., 1996;Yue et al., 1998) and several components of the mitogen-activated protein kinase (Mapk) pathways (Hartsough and Mulder, 1995;Frey and Mulder, 1997;Mulder, 2000;Sporn and Vilcek, 2000;Yue and Mulder, 2001). In addition to the Ras/Mapk and Smad pathways, several proteins have been identified based upon their interaction with the TGF␤ receptors (Yue and Mulder, 2001). Furthermore, various Smad-interacting proteins have also been identified, including SARA and Dab2, which interact with both Smads and the TGF␤ receptors (Tsukazaki et al., 1998;Hocevar et al., 2001;Yue and Mulder, 2001).Despite advances in our understanding of the mechanisms by which the Smad and Ras/Mapk cascades mediate some TGF␤ effects, these pathways seem to regulate primarily transcriptional events (Hocevar et al., 1...

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Transforming Growth Factor β Activation of p44mapk in Proliferating Cultures of Epithelial Cells

Cited by 299 publications

References 64 publications

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

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

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

A Novel Transforming Growth Factor-β Receptor-interacting Protein That Is Also a Light Chain of the Motor Protein Dynein

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