Dataset Information

?-Arrestin1 and Signal-transducing Adaptor Molecule 1 (STAM1) Cooperate to Promote Focal Adhesion Kinase Autophosphorylation and Chemotaxis via the Chemokine Receptor CXCR4.

ABSTRACT: The chemokine receptor CXCR4 and its chemokine ligand CXCL12 mediate directed cell migration during organogenesis, immune responses, and metastatic disease. However, the mechanisms governing CXCL12/CXCR4-dependent chemotaxis remain poorly understood. Here, we show that the ?-arrestin1·signal-transducing adaptor molecule 1 (STAM1) complex, initially identified to govern lysosomal trafficking of CXCR4, also mediates CXCR4-dependent chemotaxis. Expression of minigene fragments from ?-arrestin1 or STAM1, known to disrupt the ?-arrestin1·STAM1 complex, and RNAi against ?-arrestin1 or STAM1, attenuates CXCL12-induced chemotaxis. The ?-arrestin1·STAM1 complex is necessary for promoting autophosphorylation of focal adhesion kinase (FAK). FAK is necessary for CXCL12-induced chemotaxis and associates with and localizes with ?-arrestin1 and STAM1 in a CXCL12-dependent manner. Our data reveal previously unknown roles in CXCR4-dependent chemotaxis for ?-arrestin1 and STAM1, which we propose act in concert to regulate FAK signaling. The ?-arrestin1·STAM1 complex is a promising target for blocking CXCR4-promoted FAK autophosphorylation and chemotaxis.

SUBMITTER: Alekhina O

PROVIDER: S-EPMC5207078 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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β-Arrestin1 and Signal-transducing Adaptor Molecule 1 (STAM1) Cooperate to Promote Focal Adhesion Kinase Autophosphorylation and Chemotaxis via the Chemokine Receptor CXCR4.

Alekhina Olga O Marchese Adriano A

The Journal of biological chemistry 20161027 50

The chemokine receptor CXCR4 and its chemokine ligand CXCL12 mediate directed cell migration during organogenesis, immune responses, and metastatic disease. However, the mechanisms governing CXCL12/CXCR4-dependent chemotaxis remain poorly understood. Here, we show that the β-arrestin1·signal-transducing adaptor molecule 1 (STAM1) complex, initially identified to govern lysosomal trafficking of CXCR4, also mediates CXCR4-dependent chemotaxis. Expression of minigene fragments from β-arrestin1 or S ...[more]

PMID: 27789711

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Project description:Despite the crucial importance of dendritogenesis for the correct functioning of neurons, the molecular mechanisms underlying neuronal arborisation are still not well understood. Current models suggest that distinct parts and phases of dendritic development are regulated by the expression of distinct transcription factors, that are able to target the cytoskeleton. Two proteins recently implicated in dendritogenesis are the Focal Adhesion Kinase FAK1 and the Actin-binding protein Simiate. Using heterologous expression systems as well as mouse brain extracts in combination with coprecipitation assays, we show that Simiate is able to associate with FAK1. Differential centrifugation experiments further revealed the interaction to be present in cytosolic as well as nuclear fractions. Inside the nucleus though, Simiate preferentially binds to a FAK1 isoform of 80 kDa, which has previously been shown to regulate transcription factor activity. Investigating the function of both proteins in primary hippocampal cultures, we further found that FAK1 and Simiate have distinct roles in dendritogenesis: While FAK1 increases dendrite length and number, Simiate preferentially enhances growth and branching. However, if being confined to the nucleus, Simiate selectively triggers primary dendrite formation, enhancing transcription activity at the same time. Since the effect on primary dendrites is specifically re-normalized by a co-expression of FAK1 and Simiate in the nucleus, the data implies that the two proteins interact to counterbalance each other in order to control dendrite formation. Looking at the role of the cytosolic interaction of FAK1 and Simiate, we found that neurotrophin induced dendritogenesis causes a striking colocalisation of FAK1 and Simiate in dendritic growth cones, which is not present otherwise, thus suggesting that the cytosolic interaction stimulates growth cone mediated dendritogenesis in response to certain external signals. Taken together, the data show that FAK1 and Simiate exert several and distinct actions during the different phases of dendritogenesis and that these actions are related to their subcellular localisation and their interaction.

Dataset Information

?-Arrestin1 and Signal-transducing Adaptor Molecule 1 (STAM1) Cooperate to Promote Focal Adhesion Kinase Autophosphorylation and Chemotaxis via the Chemokine Receptor CXCR4.

Publications

β-Arrestin1 and Signal-transducing Adaptor Molecule 1 (STAM1) Cooperate to Promote Focal Adhesion Kinase Autophosphorylation and Chemotaxis via the Chemokine Receptor CXCR4.

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