P21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics

Jayme D. Allen; Zahara M. Jaffer; Su Jung Park; Sarah Burgin; Clemens Hofmann; Mary Ann Sells; Shi Chen; Ethel Derr-Yellin; Elizabeth G. Michels; Andrew McDaniel; Waylan K. Bessler; David A. Ingram; Simon J. Atkinson; Jeffrey B. Travers; Jonathan Chernoff; D. Wade Clapp

doi:10.1182/blood-2008-06-160861

P21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics

Jayme D. Allen, Zahara M. Jaffer, Su Jung Park, Sarah Burgin, Clemens Hofmann, Mary Ann Sells, Shi Chen, Ethel Derr-Yellin, Elizabeth G. Michels, Andrew McDaniel, Waylan K. Bessler, David A. Ingram, Simon J. Atkinson, Jeffrey B. Travers, Jonathan Chernoff, D. Wade Clapp

Cancer Signaling and Microenvironment (CSM)

Research output: Contribution to journal › Article › peer-review

104 Scopus citations

Abstract

Mast cells are key participants in allergic diseases via activation of high-affinity IgE receptors (FcεRI) resulting in release of proinflammatory mediators. The biochemical pathways linking IgE activation to calcium influx and cytoskeletal changes required for intracellular granule release are incompletely understood. We demonstrate, genetically, that Pak1 is required for this process. In a passive cutaneous anaphylaxis experiment, W ^sh/W^sh mast cell-deficient mice locally reconstituted with Pak1^-/- bone marrow-derived mast cells (BMMCs) experienced strikingly decreased allergen-induced vascular permeability compared with controls. Consistent with the in vivo phenotype, Pak1^-/- BMMCs exhibited a reduction in FcεRI-induced degranulation. Further, Pak1 ^-/- BMMCs demonstrated diminished calcium mobilization and altered depolymerization of cortical filamentous actin (F-actin) in response to FcεRI stimulation. These data implicate Pak1 as an essential molecular target for modulating acute mast cell responses that contribute to allergic diseases.

Original language	English
Pages (from-to)	2695-2705
Number of pages	11
Journal	Blood
Volume	113
Issue number	12
DOIs	https://doi.org/10.1182/blood-2008-06-160861
State	Published - Mar 19 2009

Keywords

Actins/metabolism
Adoptive Transfer
Animals
Antigens, CD/genetics
Biological Transport
Biopolymers
Bone Marrow Cells/cytology
Calcimycin/pharmacology
Calcium Signaling/drug effects
Cytoskeleton/metabolism
Enzyme Activation
Female
Immunoglobulin E/immunology
Mast Cells/metabolism
Membrane Glycoproteins/genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Passive Cutaneous Anaphylaxis/immunology
Platelet Membrane Glycoproteins
Radiation Chimera
Receptors, IgE/physiology
Recombinant Fusion Proteins/physiology
Secretory Vesicles/drug effects
Signal Transduction
Tetraspanin 30
beta-N-Acetylhexosaminidases/metabolism
p21-Activated Kinases/deficiency

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10.1182/blood-2008-06-160861

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Allen, J. D., Jaffer, Z. M., Park, S. J., Burgin, S., Hofmann, C., Sells, M. A., Chen, S., Derr-Yellin, E., Michels, E. G., McDaniel, A., Bessler, W. K., Ingram, D. A., Atkinson, S. J., Travers, J. B., Chernoff, J., & Clapp, D. W. (2009). P21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics. Blood, 113(12), 2695-2705. https://doi.org/10.1182/blood-2008-06-160861

@article{a645868d40644086845e4772b6e78653,

title = "P21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics",

abstract = "Mast cells are key participants in allergic diseases via activation of high-affinity IgE receptors (FcεRI) resulting in release of proinflammatory mediators. The biochemical pathways linking IgE activation to calcium influx and cytoskeletal changes required for intracellular granule release are incompletely understood. We demonstrate, genetically, that Pak1 is required for this process. In a passive cutaneous anaphylaxis experiment, W sh/Wsh mast cell-deficient mice locally reconstituted with Pak1-/- bone marrow-derived mast cells (BMMCs) experienced strikingly decreased allergen-induced vascular permeability compared with controls. Consistent with the in vivo phenotype, Pak1-/- BMMCs exhibited a reduction in FcεRI-induced degranulation. Further, Pak1 -/- BMMCs demonstrated diminished calcium mobilization and altered depolymerization of cortical filamentous actin (F-actin) in response to FcεRI stimulation. These data implicate Pak1 as an essential molecular target for modulating acute mast cell responses that contribute to allergic diseases.",

keywords = "Actins/metabolism, Adoptive Transfer, Animals, Antigens, CD/genetics, Biological Transport, Biopolymers, Bone Marrow Cells/cytology, Calcimycin/pharmacology, Calcium Signaling/drug effects, Cytoskeleton/metabolism, Enzyme Activation, Female, Immunoglobulin E/immunology, Mast Cells/metabolism, Membrane Glycoproteins/genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Passive Cutaneous Anaphylaxis/immunology, Platelet Membrane Glycoproteins, Radiation Chimera, Receptors, IgE/physiology, Recombinant Fusion Proteins/physiology, Secretory Vesicles/drug effects, Signal Transduction, Tetraspanin 30, beta-N-Acetylhexosaminidases/metabolism, p21-Activated Kinases/deficiency",

author = "Allen, {Jayme D.} and Jaffer, {Zahara M.} and Park, {Su Jung} and Sarah Burgin and Clemens Hofmann and Sells, {Mary Ann} and Shi Chen and Ethel Derr-Yellin and Michels, {Elizabeth G.} and Andrew McDaniel and Bessler, {Waylan K.} and Ingram, {David A.} and Atkinson, {Simon J.} and Travers, {Jeffrey B.} and Jonathan Chernoff and Clapp, {D. Wade}",

year = "2009",

month = mar,

day = "19",

doi = "10.1182/blood-2008-06-160861",

language = "English",

volume = "113",

pages = "2695--2705",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

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Allen, JD, Jaffer, ZM, Park, SJ, Burgin, S, Hofmann, C, Sells, MA, Chen, S, Derr-Yellin, E, Michels, EG, McDaniel, A, Bessler, WK, Ingram, DA, Atkinson, SJ, Travers, JB, Chernoff, J & Clapp, DW 2009, 'P21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics', Blood, vol. 113, no. 12, pp. 2695-2705. https://doi.org/10.1182/blood-2008-06-160861

TY - JOUR

T1 - P21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics

AU - Allen, Jayme D.

AU - Jaffer, Zahara M.

AU - Park, Su Jung

AU - Burgin, Sarah

AU - Hofmann, Clemens

AU - Sells, Mary Ann

AU - Chen, Shi

AU - Derr-Yellin, Ethel

AU - Michels, Elizabeth G.

AU - McDaniel, Andrew

AU - Bessler, Waylan K.

AU - Ingram, David A.

AU - Atkinson, Simon J.

AU - Travers, Jeffrey B.

AU - Chernoff, Jonathan

AU - Clapp, D. Wade

PY - 2009/3/19

Y1 - 2009/3/19

N2 - Mast cells are key participants in allergic diseases via activation of high-affinity IgE receptors (FcεRI) resulting in release of proinflammatory mediators. The biochemical pathways linking IgE activation to calcium influx and cytoskeletal changes required for intracellular granule release are incompletely understood. We demonstrate, genetically, that Pak1 is required for this process. In a passive cutaneous anaphylaxis experiment, W sh/Wsh mast cell-deficient mice locally reconstituted with Pak1-/- bone marrow-derived mast cells (BMMCs) experienced strikingly decreased allergen-induced vascular permeability compared with controls. Consistent with the in vivo phenotype, Pak1-/- BMMCs exhibited a reduction in FcεRI-induced degranulation. Further, Pak1 -/- BMMCs demonstrated diminished calcium mobilization and altered depolymerization of cortical filamentous actin (F-actin) in response to FcεRI stimulation. These data implicate Pak1 as an essential molecular target for modulating acute mast cell responses that contribute to allergic diseases.

AB - Mast cells are key participants in allergic diseases via activation of high-affinity IgE receptors (FcεRI) resulting in release of proinflammatory mediators. The biochemical pathways linking IgE activation to calcium influx and cytoskeletal changes required for intracellular granule release are incompletely understood. We demonstrate, genetically, that Pak1 is required for this process. In a passive cutaneous anaphylaxis experiment, W sh/Wsh mast cell-deficient mice locally reconstituted with Pak1-/- bone marrow-derived mast cells (BMMCs) experienced strikingly decreased allergen-induced vascular permeability compared with controls. Consistent with the in vivo phenotype, Pak1-/- BMMCs exhibited a reduction in FcεRI-induced degranulation. Further, Pak1 -/- BMMCs demonstrated diminished calcium mobilization and altered depolymerization of cortical filamentous actin (F-actin) in response to FcεRI stimulation. These data implicate Pak1 as an essential molecular target for modulating acute mast cell responses that contribute to allergic diseases.

KW - Actins/metabolism

KW - Adoptive Transfer

KW - Animals

KW - Antigens, CD/genetics

KW - Biological Transport

KW - Biopolymers

KW - Bone Marrow Cells/cytology

KW - Calcimycin/pharmacology

KW - Calcium Signaling/drug effects

KW - Cytoskeleton/metabolism

KW - Enzyme Activation

KW - Female

KW - Immunoglobulin E/immunology

KW - Mast Cells/metabolism

KW - Membrane Glycoproteins/genetics

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Passive Cutaneous Anaphylaxis/immunology

KW - Platelet Membrane Glycoproteins

KW - Radiation Chimera

KW - Receptors, IgE/physiology

KW - Recombinant Fusion Proteins/physiology

KW - Secretory Vesicles/drug effects

KW - Signal Transduction

KW - Tetraspanin 30

KW - beta-N-Acetylhexosaminidases/metabolism

KW - p21-Activated Kinases/deficiency

UR - http://www.scopus.com/inward/record.url?scp=63849230362&partnerID=8YFLogxK

U2 - 10.1182/blood-2008-06-160861

DO - 10.1182/blood-2008-06-160861

M3 - Article

C2 - 19124833

SN - 0006-4971

VL - 113

SP - 2695

EP - 2705

JO - Blood

JF - Blood

IS - 12

ER -

P21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics

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Keywords

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