Rap1: A turnabout for the crosstalk between cadherins and integrins

Retta, Saverio Francesco; Balzac, Fiorella; Avolio, Maria

doi:10.1016/j.ejcb.2005.09.007

Cited by 79 publications

(76 citation statements)

References 82 publications

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“…Signaling through Rap1 has been the subject of intense study, as activation of this cascade is thought to play an important role in cell adhesion (23,24), polarity (25), and secretion (26,27). The mode, specificity, and localization of Rap1 action is determined by the presence of various upstream Rap1 GEFs and GAPs and downstream effector proteins.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Rap1GAP, a striatally enriched protein, by protein kinase A controls Rap1 activity and dendritic spine morphology

McAvoy

Zhou

Greengard

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Protein kinase A (PKA)-dependent signaling cascades play an important role in mediating the effects of dopamine and other neurotransmitters in striatal medium spiny neurons. We have identified a prominent striatal PKA substrate as Rap1-GTPase activating protein (Rap1GAP), a negative regulator of Rap1 signaling. Although present throughout the brain, Rap1GAP is enriched in striatal medium spiny neurons and is phosphorylated by PKA at Ser-441 and Ser-499 in response to activation of D1 dopamine receptors. Phosphorylation of Rap1GAP is associated with inhibition of GAP activity, as demonstrated by increased Rap1 activity in striatal neurons. Phosphorylation of Rap1GAP is also associated with increased dendritic spine head size in cultured neurons. These findings suggest that phosphorylation of Rap1GAP by PKA plays an important role in striatal neurons by modulating Rap1 actions.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of Rap1GAP, a striatally enriched protein, by protein kinase A controls Rap1 activity and dendritic spine morphology

McAvoy

Zhou

Greengard

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…The significance of these divergent effects upon SIPA1 is particularly intriguing, especially as both Brd4 and Rrp1b appear to have similar effects upon tumor progression. RAP1 activity has been shown to play an important role in metastasis [35,36]. Therefore, it appears crucial at this stage that we further investigate the BRD4-SIPA1-RRP1B relationship and the influence that it has upon RAP1 levels within the tumor cell to determine whether the effects of these factors are dependent or independent of this system.…”

Section: Discussionmentioning

confidence: 99%

The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival

Crawford

Walker

Lukes

et al. 2008

Clin Exp Metastasis

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Microarray expression signature analyses have suggested that extracellular matrix (ECM) gene dysregulation is predictive of metastasis in both mouse mammary tumorigenesis and human breast cancer. We have previously demonstrated that such ECM dysregulation is influenced by hereditary germline-encoded variation. To identify novel metastasis efficiency modifiers, we performed expression QTL (eQTL) mapping in recombinant inbred mice by characterizing genetic loci modulating metastasis-predictive ECM gene expression. Three reproducible eQTLs were observed on chromosomes 7, 17 and 18. Candidate genes were identified by correlation analyses and known associations with metastasis. Seven candidates were identified (Ndn, Pi16, Luc7l, Rrp1b, Brd4, Centd3 and Csf1r). Stable transfection of the highly metastatic Mvt-1 mouse mammary tumor cell line with expression vectors encoding each candidate modulated metastasis-predictive ECM gene expression. Implantation of these cells into mice demonstrated that candidate gene ectopic expression impacts tumor progression. Gene expression analyses facilitated the construction of a transcriptional network that we have termed the 'Diasporin Pathway'. This pathway contains the seven candidates, as well as metastasis-predictive ECM genes and metastasis suppressors. Brd4 and Rrp1b appear to form a central node within this network, which likely is a consequence of their physical interaction with the metastasis efficiency modifier Sipa1. Furthermore, we demonstrate that the microarray gene expression signatures induced by activation of ECM eQTL genes in the Mvt-1 cell line can be used to accurately predict survival in a human breast cancer cohort. These data imply that the Diasporin Pathway may be an important nexus in tumor progression in both mice and humans.

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“…At the molecular level, this has been linked to the small GTPase Rap1, a mediator of integrin inside-out activation 10,50 . Rap1 can also promote cell junction formation 48,51 and, according to our data, might mediate bidirectional cross-talk between cadherins and integrins in ECs. Rap1 and the kinase MRCK, as well as Rho/Rho-kinase, appear to act redundantly in the control of actomyosin contractility downstream of integrins.…”

Section: Discussionmentioning

confidence: 99%

“…Previous work on other members of the cadherin family, in most cases E-cadherin, has shown that these adhesion molecules can control integrin activity 48,49 . At the molecular level, this has been linked to the small GTPase Rap1, a mediator of integrin inside-out activation 10,50 .…”

Section: Discussionmentioning

confidence: 99%

Integrin β1 controls VE-cadherin localization and blood vessel stability

et al. 2015

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Angiogenic blood vessel growth requires several distinct but integrated cellular activities. Endothelial cell sprouting and proliferation lead to the expansion of the vasculature and give rise to a highly branched, immature plexus, which is subsequently reorganized into a mature and stable network. Although it is known that integrin-mediated cell-matrix interactions are indispensable for embryonic angiogenesis, little is known about the function of integrins in different steps of vascular morphogenesis. Here, by investigating the integrin b1-subunit with inducible and endothelial-specific gene targeting in the postnatal mouse retina, we show that b1 integrin promotes endothelial sprouting but is a negative regulator of proliferation. In maturing vessels, integrin b1 is indispensable for proper localization of VE-cadherin and thereby cell-cell junction integrity. The sum of our findings establishes that integrin b1 has critical functions in the growing and maturing vasculature, and is required for the formation of stable, non-leaky blood vessels.

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Rap1: A turnabout for the crosstalk between cadherins and integrins

Cited by 79 publications

References 82 publications

Phosphorylation of Rap1GAP, a striatally enriched protein, by protein kinase A controls Rap1 activity and dendritic spine morphology

Phosphorylation of Rap1GAP, a striatally enriched protein, by protein kinase A controls Rap1 activity and dendritic spine morphology

The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival

Integrin β1 controls VE-cadherin localization and blood vessel stability

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