A Rap/Phosphatidylinositol 3-Kinase Pathway Controls Pseudopod Formation

Kortholt, Arjan; Bolourani, Parvin; Rehmann, Holger; Keizer‐Gunnink, Ineke; Weeks, Gerald; Wittinghofer, Alfred; Haastert, Peter J.M. van

doi:10.1091/mbc.e09-03-0177

Cited by 46 publications

(53 citation statements)

References 62 publications

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“…It has been reported that Ras C and Ras G null cells are capable of chemotaxis, however, Ras C/G double nulls are completely blind in a cAMP gradient and together are required for directed migration (Bolourani et al, 2006). Ras G is thought to regulate the production of PtdIns(3,4,5)P 3 by activating PI3K at the leading edge during cAMP-mediated chemotaxis (Kamimura et al, 2008;Kortholt et al, 2010;Charest et al, 2010). In these studies, cAR1 expression was significantly reduced and delayed during early development in Ras G null cells and undetectable in Ras C/G double null cells (Bolourani et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

Delineating the core regulatory elements crucial for directed cell migration by examining folic-acid-mediated responses

Srinivasan

Wright

Hames

et al. 2013

Journal of Cell Science

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SummaryDictyostelium discoideum shows chemotaxis towards folic acid (FA) throughout vegetative growth, and towards cAMP during development. We determined the spatiotemporal localization of cytoskeletal and signaling molecules and investigated the FA-mediated responses in a number of signaling mutants to further our understanding of the core regulatory elements that are crucial for cell migration. Proteins enriched in the pseudopods during chemotaxis also relocalize transiently to the plasma membrane during uniform FA stimulation. In contrast, proteins that are absent from the pseudopods during migration redistribute transiently from the PM to the cytosol when cells are globally stimulated with FA. These chemotactic responses to FA were also examined in cells lacking the GTPases Ras C and G. Although Ras and phosphoinositide 3-kinase activity were significantly decreased in Ras G and Ras C/G nulls, these mutants still migrated towards FA, indicating that other pathways must support FA-mediated chemotaxis. We also examined the spatial movements of PTEN in response to uniform FA and cAMP stimulation in phospholipase C (PLC) null cells. The lack of PLC strongly influences the localization of PTEN in response to FA, but not cAMP. In addition, we compared the gradient-sensing behavior of polarized cells migrating towards cAMP to that of unpolarized cells migrating towards FA. The majority of polarized cells make U-turns when the cAMP gradient is switched from the front of the cell to the rear. Conversely, unpolarized cells immediately extend pseudopods towards the new FA source. We also observed that plasma membrane phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P 3 ] levels oscillate in unpolarized cells treated with Latrunculin-A, whereas polarized cells had stable plasma membrane PtdIns(3,4,5)P 3 responses toward the chemoattractant gradient source. Results were similar for cells that were starved for 4 hours, with a mixture of polarized and unpolarized cells responding to cAMP. Taken together, these findings suggest that similar components control gradient sensing during FA-and cAMP-mediated motility, but the response of polarized cells is more stable, which ultimately helps maintain their directionality.

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Section: Resultsmentioning

confidence: 99%

Delineating the core regulatory elements crucial for directed cell migration by examining folic-acid-mediated responses

Srinivasan

Wright

Hames

et al. 2013

Journal of Cell Science

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“…Data are representative of at least three independent experiments. Sasaki et al, 2004), RasC is the main activator of TORC2 (Cai et al, 2010;Charest et al, 2010), and Rap1 has been shown to regulate the activity of both PI3K and TORC2 (Khanna et al, 2016;Kortholt et al, 2010) in addition to other Rap1 effectors. To then investigate potential mechanisms underlying the elevated activity levels of TORC2 and PI3K in cells that lack PKA function, we examined the activity of RasC, RasG and Rap1 under such conditions.…”

Section: Lack Of Pka Function Has Different Effects On Rasc Rasg Andmentioning

confidence: 99%

“…Rap1 controls cell-substrate adhesion and cell polarity by promoting remodeling of both actin and myosin, in part, through phosphoinositide 3-kinase (PI3K), Rac, the serine/ threonine kinase Phg2, as well as through the regulation of the Target of Rapamycin Complex 2 (TORC2) (Jeon et al, 2007a;Khanna et al, 2016;Kortholt et al, 2006Kortholt et al, , 2010Mun and Jeon, 2012;Plak et al, 2013). RasG activates PI3K, thereby controlling the site of F-actin polymerization and the direction of migration (Bolourani et al, 2006;Sasaki et al, 2004;Zhang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Protein kinase A regulates the Ras, Rap1 and TORC2 pathways in response to the chemoattractant cAMP in Dictyostelium

Scavello

Petlick

Ramesh

et al. 2017

Journal of Cell Science

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Efficient directed migration requires tight regulation of chemoattractant signal transduction pathways in both space and time, but the mechanisms involved in such regulation are not well understood. Here, we investigated the role of protein kinase A (PKA) in controlling signaling of the chemoattractant cAMP in Dictyostelium discoideum. We found that cells lacking PKA display severe chemotaxis defects, including impaired directional sensing. Although PKA is an important regulator of developmental gene expression, including the cAMP receptor cAR1, our studies using exogenously expressed cAR1 in cells lacking PKA, cells lacking adenylyl cyclase A (ACA) and cells treated with the PKA-selective pharmacological inhibitor H89, suggest that PKA controls chemoattractant signal transduction, in part, through the regulation of RasG, Rap1 and TORC2. As these pathways control the ACAmediated production of intracellular cAMP, they lie upstream of PKA in this chemoattractant signaling network. Consequently, we propose that the PKA-mediated regulation of the upstream RasG, Rap1 and TORC2 signaling pathways is part of a negative feedback mechanism controlling chemoattractant signal transduction during Dictyostelium chemotaxis.

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“…Stimulation of PI3K, induced by Rap1, activates Rac1, cell adhesion and pseudopod formation. 34 In addition, ILK is a regulator of adhesion, cell spreading, migration through integrin activation modulating intracellular signaling pathways, and recruiting molecules involved in actin polymerization. 29,35,36 Similarly, lenalidomide was reported to target Rho GTPase signaling and to promote Rap1 trafficking to the membrane, restoring the adhesion and motility function of T cells from CLL patients.…”

Section: Discussionmentioning

confidence: 99%

Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia

et al. 2014

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Patients and samplesWritten informed consent was obtained in accordance with the Declaration of Helsinki with a protocol approved by the local Institutional Review Board. CD14 + monocytes were obtained by immunomagnetic selection. To generate NLCs, PBMCs from CLL patients were cultured (10 7 /mL) as previously described. 18Lenalidomide was used at the clinically relevant doses of 0.5 mM, 1 mM and 10 mM as in previous studies.

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A Rap/Phosphatidylinositol 3-Kinase Pathway Controls Pseudopod Formation

Cited by 46 publications

References 62 publications

Delineating the core regulatory elements crucial for directed cell migration by examining folic-acid-mediated responses

Delineating the core regulatory elements crucial for directed cell migration by examining folic-acid-mediated responses

Protein kinase A regulates the Ras, Rap1 and TORC2 pathways in response to the chemoattractant cAMP in Dictyostelium

Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia

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