Dataset Information

Central role of PI3K-SYK interaction in fibrinogen-induced lamellipodia and filopodia formation in platelets.

ABSTRACT: The WAVE complex-1, a complex of WAVE, Abi1, NAP1, PIR121, HSPC300, RacGTP and Arp2/3 proteins, and WASP complex-1, a complex of WASP, Cdc42, PIP2, and Arp2/3 proteins, are involved in lamellipodia and filopodia formation, respectively. It is known that the two complexes have opposite dynamics. Furthermore, Rac has two guanine nucleotide exchange factors, Vav and Sos, whose role in activating Rac is not well understood. In this work, by the construction of signaling network, analysis, and mathematical modeling, I show that Sos generates a pulse of WAVE complex-1, decreasing the response time of WAVE complex-1 formation upon the stimulation of platelets by fibrinogen. Furthermore, I also show that the dynamics of WAVE and WASP complexes depends on PI3K-SYK interaction. In the absence of this interaction, the WAVE complex-1 does not form and the WASP complex-1 remains at the initial, sustained level. Thus, I show the significance of the two protein/protein complexes: Sos and PI3K-SYK interaction, in fibrinogen-induced lamellipodia and filopodia formation in platelets.

SUBMITTER: Singh R

PROVIDER: S-EPMC5324771 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Central role of PI3K-SYK interaction in fibrinogen-induced lamellipodia and filopodia formation in platelets.

Singh Raghvendra R

FEBS open bio 20161123 12

The WAVE complex-1, a complex of WAVE, Abi1, NAP1, PIR121, HSPC300, RacGTP and Arp2/3 proteins, and WASP complex-1, a complex of WASP, Cdc42, PIP2, and Arp2/3 proteins, are involved in lamellipodia and filopodia formation, respectively. It is known that the two complexes have opposite dynamics. Furthermore, Rac has two guanine nucleotide exchange factors, Vav and Sos, whose role in activating Rac is not well understood. In this work, by the construction of signaling network, analysis, and mathem ...[more]

PMID: 28255536

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Project description:BACKGROUND & AIMS:Sperm flagellar 1 (also called CLAMP) is a microtubule-associated protein that regulates microtubule dynamics and planar cell polarity in multi-ciliated cells. We investigated the localization and function of sperm flagellar 1, or CLAMP, in human intestinal epithelia cells (IECs). METHODS:We performed studies with SKCO-15 and human intestinal enteroids established from biopsies from different intestinal segments (duodenal, jejunum, ileal, and colon) of a single donor. Enteroids were induced to differentiation after incubation with growth factors. The distribution of endogenous CLAMP in IECs was analyzed by immunofluorescence microscopy using total internal reflection fluorescence-ground state depletion and confocal microscopy. CLAMP localization was followed during the course of intestinal epithelial cell polarization as cells progressed from flat to compact, confluent monolayers. Protein interactions with endogenous CLAMP were determined in SKCO-15 cells using proximity ligation assays and co-immunoprecipitation. CLAMP was knocked down in SKCO-15 monolayers using small hairpin RNAs and cells were analyzed by immunoblot and immunofluorescence microscopy. The impact of CLAMP knock-down in migrating SKCO-15 cells was assessed using scratch-wound assays. RESULTS:CLAMP bound to actin and apical junctional complex proteins but not microtubules in IECs. In silico analysis predicted the calponin-homology domain of CLAMP to contain conserved amino acids required for actin binding. During IEC polarization, CLAMP distribution changed from primarily basal stress fibers and cytoplasm in undifferentiated cells to apical membranes and microvilli in differentiated monolayers. CLAMP accumulated in lamellipodia and filopodia at the leading edge of migrating cells in association with actin. CLAMP knock-down reduced the number of filopodia, perturbed filopodia polarity, and altered the organization of actin filaments within lamellipodia. CONCLUSIONS:CLAMP is an actin-binding protein, rather than a microtubule-binding protein, in IECs. CLAMP distribution changes during intestinal epithelial cell polarization, regulates the formation of filopodia, and appears to assist in the organization of actin bundles within lamellipodia of migrating IECs. Studies are needed to define the CLAMP domains that interact with actin and whether its loss from IECs affects intestinal function.

Dataset Information

Central role of PI3K-SYK interaction in fibrinogen-induced lamellipodia and filopodia formation in platelets.

Publications

Central role of PI3K-SYK interaction in fibrinogen-induced lamellipodia and filopodia formation in platelets.

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