Growth control in mammalian cells by cell-cell contacts.

Wieser, Raimund; Renauer, Doris; Schäfer, Anke; Heck, Rosario; Engel, Renate; Schütz, Sonja; Oesch, Franz

doi:10.1289/ehp.9088251

Cited by 27 publications

(10 citation statements)

References 22 publications

(19 reference statements)

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“…We have also observed a GH-dependent association between Rap1 and actin by co-immunoprecipitation. 2 Proliferation of NIH-3T3 cells is known to be highly sensitive to contact inhibition (50). In this regard it is interesting that we have observed that autocrine production of GH in human mammary carcinoma cells results in disassembly of adherens junctions and loss of intercellular contact.…”

Section: Discussionmentioning

confidence: 99%

Src-CrkII-C3G-dependent Activation of Rap1 Switches Growth Hormone-stimulated p44/42 MAP Kinase and JNK/SAPK Activities

Ling

Zhu

Lobie

2003

Journal of Biological Chemistry

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We demonstrate here that growth hormone (GH) stimulates the activation of Rap1 and Rap2 in NIH-3T3 cells. Full activation of Rap1 and Rap2 by GH necessitated the combined activity of both JAK2 and c-Src kinases, although c-Src was predominantly required. GH-stimulated Rap1 and Rap2 activity was also demonstrated to be CrkII-C3G-dependent. GH stimulated the tyrosine phosphorylation of C3G, which again required the combined activity of JAK2 and c-Src. C3G tyrosine residue 504 was required for GH-stimulated Rap activation. Activated Rap1 inhibited GH-stimulated activation of RalA and subsequent GH-stimulated p44/42 MAP kinase activity and Elk-1-mediated transcription. In addition, we demonstrated that C3G-Rap1 mediated CrkII enhancement of GH-stimulated JNK/SAPK activity. We have therefore identified a linear JAK2-independent pathway switching GH-stimulated p44/42 MAP kinase and JNK/SAPK activities.The Rap proteins (Rap1 and Rap2) belong to the Ras-like small GTPase superfamily, which consists of at least 13 members (1). In this family, Ras has been extensively studied and was originally regarded as a transforming oncogene since Ras genes have been found mutated in about 15% of all human tumors (2). It possesses an important role in cell growth and differentiation as it has been demonstrated to be required for activation of p44/42 MAP 1 kinase activity by a number of growth factors including growth hormone (GH) (3-5). Rap1 is closely related to Ras and was initially identified as a suppressor of the K-ras transformed phenotype (6). Structurally, Rap1 shares striking similarity with Ras in the effector domain. It has been suggested that Rap1 antagonizes Ras activity by sequestration of its target, Raf-1, in the inactive form (7). In addition, several studies have demonstrated that both Rap1 and Ras can bind the same effectors, such as Raf-1 and RalGDS (8). Rap2 exhibits 60% identity to Rap1 and shares most of the effector proteins with Ras and Rap1 (9). The function of Rap2 is more limited compared with Rap1, although an antagonistic effect of Rap2 on Ras-mediated transcription has been reported (10).One common mechanism utilized by small GTPases to regulate cellular function is to cycle between the inactive GDPbound state and the active GTP-bound state. Guanine nucleotide exchange factors (GEFs) facilitate GDP dissociation and allow the more abundant GTP to rebind, while GTPase-activating proteins (GAPs) accelerate GTP hydrolysis to complete the cycle (1, 7). C3G is a Rap-specific GEF since it predominantly catalyzes the guanine nucleotide exchange reaction for Rap1 and Rap2 (10, 11). C3G was originally identified as a major protein bound to the SH3 domain of c-Crk (12). There are three proline-rich sequences that bind to the SH3 domain of c-Crk in the central region of C3G and one C-terminal CDC25 homology domain catalyzing the GEF reaction of Rap (13). The function of the C3G N terminus remains unknown but recent studies have reported the association of p130cas to this region (14). C3G is activated by c-Crk-media...

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Section: Discussionmentioning

confidence: 99%

Src-CrkII-C3G-dependent Activation of Rap1 Switches Growth Hormone-stimulated p44/42 MAP Kinase and JNK/SAPK Activities

Ling

Zhu

Lobie

2003

Journal of Biological Chemistry

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“…Normal adherent cells as well as some immortalized cell lines exit the cell cycle and stop proliferating when grown to confluence, even in the presence of optimal amounts of growth factors. This contact-dependent control of cell proliferation is believed to act in vivo during tissue regeneration and wound healing and is also conceivably involved in tissue patterning during embryonic development (14).…”

Section: From the Institute Of General Pathology Catholic Universitymentioning

confidence: 99%

A Redox Signaling Mechanism for Density-dependent Inhibition of Cell Growth

Pani

Colavitti

Bedogni

et al. 2000

Journal of Biological Chemistry

154

105

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Reactive oxygen species (ROS) have recently drawn significant attention as putative mitogenic mediators downstream of activated growth factor receptors and oncogenic Ras; however, the possibility that a redoxrelated mechanism also operates in the negative control of cell proliferation by inhibitory signals has not been investigated thus far. Here we show that the arrest of growth induced by cell confluence ("contact inhibition") is due, at least in part, to a decrease in the steady-state levels of intracellular ROS and the consequent impairment of mitogenic redox signaling. In confluent fibroblast cultures, the decrease in the concentration of oxygen species was associated with diminished activity of the small GTPase Rac-1, a signal transducer directly involved in the ligand-dependent generation of oxygenderived molecules, and was effectively mimicked by exposure of sparse cultures to dithiothreitol (DTT) and inhibitors of enzymes (phospholipase A2 and lipoxygenase) acting in the arachidonic acid cascade downstream of growth factor receptors and Rac-1. Sparse fibroblasts treated with nontoxic amounts of DTT underwent growth arrest, whereas a low concentration of hydrogen peroxide significantly increased thymidine incorporation in confluent cultures, demonstrating a causal link between redox changes and growth control by cell density. Removal of oxygen species from sparse cultures was accompanied by a drastic decrease of protein tyrosine phosphorylation after epidermal growth factor stimulation, which, at a biochemical level, reproduced the signaling hallmarks of contact inhibition. Moreover, the cytosolic tyrosine phosphatase SHP-2 was identified as a putative target for redox signaling by cell density because the enzyme itself and the associated substrates appear markedly dephosphorylated in both confluent and reductant-treated cells after exposure to epidermal growth factor, and SHP-2 enzymatic activity is strongly activated by DTT in vitro. Taken together, these data support a model in which impaired generation of ROS and increased protein tyrosine phosphatase activity impede mitogenic signaling in contact-inhibited cells.Significant evidence points to a role for oxygen-derived reactive species (ROS) 1 as mitogens for mammalian cells; this possibility is suggested by the fact that exogenous oxidants can induce the entry of quiescent cells into cell cycle (1) and are able to elicit signal transduction events, such as protein tyrosine phosphorylation and early gene activation, reminiscent of cell stimulation by growth factors (2). More importantly, "traditional" proliferative signals, such as those delivered by the activation of growth factor receptors and G proteins of the Ras family, are accompanied by intracellular production of endogenous oxygen species, which are, in turn, necessary for downstream propagation of mitogenic signaling. In fact, ROS and hydrogen peroxide, in particular, have been convincingly shown to operate as key signaling molecules in the cascades triggered by platelet-derived growth facto...

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“…In high-density cultures when proliferation is reduced the oligodendrocyte precursors form an almost confluent monolayer suggesting that the signal mediating the reduction in proliferation is contact dependent. The notion of contact inhibition of cell proliferation is not new [Wieser et al, 1990]. Studies on a number of different cell types suggest that cell-cell interactions mediated by specific cell surface glycoproteins result in an inhibition of cell proliferation [Wieser et al, 1990].…”

Section: Discussionmentioning

confidence: 99%

“…The notion of contact inhibition of cell proliferation is not new [Wieser et al, 1990]. Studies on a number of different cell types suggest that cell-cell interactions mediated by specific cell surface glycoproteins result in an inhibition of cell proliferation [Wieser et al, 1990]. In the vertebrate CNS, interactions between different cells control cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Control of Oligodendrocyte Precursor Proliferation Mediated by Density-Dependent Cell Cycle Protein Expression

Nakatsuji

Miller

2001

Dev Neurosci

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The proliferation of oligodendrocyte precursors is closely regulated in the developing vertebrate CNS. In previous studies we have demonstrated a cell-type-specific density-dependent feedback mechanism that contributes to the control of oligodendrocyte progenitor cell clonal expansion in vitro. Here we demonstrate a density-dependent reduction in the proliferation of oligodendrocyte precursors. This inhibition of proliferation is correlated with increases in expression levels of the cell cycle inhibitor p27^Kip1, reductions in the expression of cyclin A and changes in the relative phosphorylation levels of Rb. These changes are reversible on replating at low density suggesting that additional signals are required for terminal oligodendrocyte differentiation.

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Growth control in mammalian cells by cell-cell contacts.

Cited by 27 publications

References 22 publications

Src-CrkII-C3G-dependent Activation of Rap1 Switches Growth Hormone-stimulated p44/42 MAP Kinase and JNK/SAPK Activities

Src-CrkII-C3G-dependent Activation of Rap1 Switches Growth Hormone-stimulated p44/42 MAP Kinase and JNK/SAPK Activities

A Redox Signaling Mechanism for Density-dependent Inhibition of Cell Growth

Control of Oligodendrocyte Precursor Proliferation Mediated by Density-Dependent Cell Cycle Protein Expression

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