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MenaINV mediates synergistic cross-talk between signaling pathways driving chemotaxis and haptotaxis.

ABSTRACT: Directed cell migration, a key process in metastasis, arises from the combined influence of multiple processes, including chemotaxis-the directional movement of cells to soluble cues-and haptotaxis-the migration of cells on gradients of substrate-bound factors. However, it is unclear how chemotactic and haptotactic pathways integrate with each other to drive overall cell behavior. Mena^INV has been implicated in metastasis by driving chemotaxis via dysregulation of phosphatase PTP1B and more recently in haptotaxis via interaction with integrin ?5?1. Here we find that Mena^INV-driven haptotaxis on fibronectin (FN) gradients requires intact signaling between ?5?1 integrin and the epidermal growth factor receptor (EGFR), which is influenced by PTP1B. Furthermore, we show that Mena^INV-driven haptotaxis and ECM reorganization both require the Rab-coupling protein RCP, which mediates ?5?1 and EGFR recycling. Finally, Mena^INV promotes synergistic migratory response to combined EGF and FN in vitro and in vivo, leading to hyperinvasive phenotypes. Together our data demonstrate that Mena^INV is a shared component of multiple prometastatic pathways that amplifies their combined effects, promoting synergistic cross-talk between RTKs and integrins.

SUBMITTER: Oudin MJ

PROVIDER: S-EPMC5063616 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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MenaINV mediates synergistic cross-talk between signaling pathways driving chemotaxis and haptotaxis.

Oudin Madeleine J MJ Miller Miles A MA Klazen Joelle A Z JA Kosciuk Tatsiana T Lussiez Alisha A Hughes Shannon K SK Tadros Jenny J Bear James E JE Lauffenburger Douglas A DA Gertler Frank B FB

Molecular biology of the cell 20160824 20

Directed cell migration, a key process in metastasis, arises from the combined influence of multiple processes, including chemotaxis-the directional movement of cells to soluble cues-and haptotaxis-the migration of cells on gradients of substrate-bound factors. However, it is unclear how chemotactic and haptotactic pathways integrate with each other to drive overall cell behavior. Mena<sup>INV</sup> has been implicated in metastasis by driving chemotaxis via dysregulation of phosphatase PTP1B an ...[more]

PMID: 27559126

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Project description:Chemotaxis is the process by which motile bacteria sense their chemical environment and move towards more favourable conditions. Escherichia coli utilises a single sensory pathway, but little is known about signalling pathways in species with more complex systems.To investigate whether chemotaxis pathways in other bacteria follow the E. coli paradigm, we analysed 206 species encoding at least 1 homologue of each of the 5 core chemotaxis proteins (CheA, CheB, CheR, CheW and CheY). 61 species encode more than one of all of these 5 proteins, suggesting they have multiple chemotaxis pathways. Operon information is not available for most bacteria, so we developed a novel statistical approach to cluster che genes into putative operons. Using operon-based models, we reconstructed putative chemotaxis pathways for all 206 species. We show that cheA-cheW and cheR-cheB have strong preferences to occur in the same operon as two-gene blocks, which may reflect a functional requirement for co-transcription. However, other che genes, most notably cheY, are more dispersed on the genome. Comparison of our operons with shuffled equivalents demonstrates that specific patterns of genomic location may be a determining factor for the observed in vivo chemotaxis pathways. We then examined the chemotaxis pathways of Rhodobacter sphaeroides. Here, the PpfA protein is known to be critical for correct partitioning of proteins in the cytoplasmically-localised pathway. We found ppfA in che operons of many species, suggesting that partitioning of cytoplasmic Che protein clusters is common. We also examined the apparently non-typical chemotaxis components, CheA3, CheA4 and CheY6. We found that though variants of CheA proteins are rare, the CheY6 variant may be a common type of CheY, with a significantly disordered C-terminal region which may be functionally significant.We find that many bacterial species potentially have multiple chemotaxis pathways, with grouping of che genes into operons likely to be a major factor in keeping signalling pathways distinct. Gene order is highly conserved with cheA-cheW and cheR-cheB blocks, perhaps reflecting functional linkage. CheY behaves differently to other Che proteins, both in its genomic location and its putative protein interactions, which should be considered when modelling chemotaxis pathways.

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MenaINV mediates synergistic cross-talk between signaling pathways driving chemotaxis and haptotaxis.

Publications

MenaINV mediates synergistic cross-talk between signaling pathways driving chemotaxis and haptotaxis.

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