α-AP-2 Directs Myosin VI-dependent Endocytosis of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels in the Intestine

Collaco, Anne; Jakab, Robert L.; Hegan, Peter S.; Mooseker, Mark S.; Ameen, Nadia

doi:10.1074/jbc.m110.127613

Cited by 54 publications

(70 citation statements)

References 35 publications

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“…In non-epithelial cells, AP-2 is necessary for efficient CFTR endocytosis, and the 2 adaptin interacts directly with the CFTR YDSI motif in vitro (10,20,21). Thus, in HEK293 cells, even a modest 64% knockdown of ␣-AP-2 caused a 2-fold reduction in the endocytic uptake of CFTR (18). In comparison, the situation in airway epithelial cells is less clear.…”

mentioning

confidence: 87%

“…Because nearly complete depletion of AP-2 can affect both CCV formation and cargo recruitment (17), we aimed for a less profound inhibition of CCV formation to test the specificity of AP-2 in recruiting CFTR to CCVs in polarized human airway epithelial cells. A similar approach was previously used to test the role of AP-2 in non-epithelial systems (18). Because the 2 adaptin is unique to AP-2, we therefore used a siRNA targeting a non-conserved region of the human 2 adaptin gene (si2) to specifically inhibit AP-2 assembly.…”

Section: Partial Silencing Of Dab2 But Not Ap-2 Increases Plasma Mementioning

confidence: 99%

“…CFTR co-immunoprecipitated with Dab2 and myosin VI in human airway epithelial cells (23) and colocalized with Dab2, AP-2, and myosin VI in rat enterocytes (18). CFTR abundance was increased in the intestines of Dab2 KO mice, and CFTR endocytosis was inhibited after Dab2 depletion in human airway epithelial cells (18,19). However, little is known about the specific mechanism whereby Dab2 facilitates CFTR endocytosis.…”

mentioning

confidence: 99%

“…However, little is known about the specific mechanism whereby Dab2 facilitates CFTR endocytosis. CFTR does not contain a canonical NPXY motif, and it has thus been proposed that its role is dependent on interactions with AP-2 and/or other endocytic adaptors, such as myosin VI (18,19). No published studies addressed directly whether Dab2 can recruit CFTR to clathrin coats independent of AP-2 and thus facilitate CFTR endocytosis in airway epithelial cells.…”

mentioning

confidence: 99%

“…AP-2 has clearly been shown to play a role in CFTR endocytosis in cells that endogenously express the channel (14,18,19). In non-epithelial cells, AP-2 is necessary for efficient CFTR endocytosis, and the 2 adaptin interacts directly with the CFTR YDSI motif in vitro (10,20,21).…”

mentioning

confidence: 99%

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Disabled-2 Protein Facilitates Assembly Polypeptide-2-independent Recruitment of Cystic Fibrosis Transmembrane Conductance Regulator to Endocytic Vesicles in Polarized Human Airway Epithelial Cells

Cihil

Ellinger

Fellows

et al. 2012

Journal of Biological Chemistry

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mentioning

confidence: 87%

Section: Partial Silencing Of Dab2 But Not Ap-2 Increases Plasma Mementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Disabled-2 Protein Facilitates Assembly Polypeptide-2-independent Recruitment of Cystic Fibrosis Transmembrane Conductance Regulator to Endocytic Vesicles in Polarized Human Airway Epithelial Cells

Cihil

Ellinger

Fellows

et al. 2012

Journal of Biological Chemistry

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TheMYO6 interactome: selective motor‐cargo complexes for diverse cellular processes

et al. 2019

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Myosins of class VI (MYO6) are unique actin‐based motor proteins that move cargo towards the minus ends of actin filaments. As the sole myosin with this directionality, it is critically important in a number of biological processes. Indeed, loss or overexpression of MYO6 in humans is linked to a variety of pathologies including deafness, cardiomyopathy, neurodegenerative diseases as well as cancer. This myosin interacts with a wide variety of direct binding partners such as for example the selective autophagy receptors optineurin, TAX1BP1 and NDP52 and also Dab2, GIPC, TOM1 and LMTK2, which mediate distinct functions of different MYO6 isoforms along the endocytic pathway. Functional proteomics has recently been used to identify the wider MYO6 interactome including several large functionally distinct multi‐protein complexes, which highlight the importance of this myosin in regulating the actin and septin cytoskeleton. Interestingly, adaptor‐binding not only triggers cargo attachment, but also controls the inactive folded conformation and dimerisation of MYO6. Thus, the C‐terminal tail domain mediates cargo recognition and binding, but is also crucial for modulating motor activity and regulating cytoskeletal track dynamics.

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Disabled‐2: A modular scaffold protein with multifaceted functions in signaling

Finkielstein

Capelluto

2016

BioEssays

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Disabled-2 (Dab2) is a multimodular scaffold protein with signaling roles in the domains of cell growth, trafficking, differentiation, and homeostasis. Emerging evidences place Dab2 as a novel modulator of cell-cell interaction; however, its mode of action has remained largely elusive. In this review, we highlight the relevance of Dab2 function in cell signaling and development and provide the most recent and comprehensive analysis of Dab2's action as a mediator of homotypical and heterotypical interactions. Accordingly, Dab-2 controls the extent of platelet aggregation through various motifs within its N-terminus. Dab2 interacts with the cytosolic tail of the integrin receptor blocking inside-out signaling, whereas extracellular Dab2 competes with fibrinogen for integrin α IIb β 3 receptor binding and, thus, modulates outside-in signaling. An additional level of regulation results from Dab2's association with cell surface lipids, an event that defines the extent of cell-cell interactions. As a multifaceted regulator, Dab2 acts as a mediator of endocytosis through its association with the [FY]xNPx[YF] motifs of internalized cell surface receptors, phosphoinositides, and clathrin. Other emerging roles of Dab2 include its participation in developmental mechanisms required for tissue formation and in modulation of immune responses. This review highlights the various novel mechanisms by which Dab2 mediates an array of signaling events with vast physiological consequences.

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α-AP-2 Directs Myosin VI-dependent Endocytosis of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels in the Intestine

Cited by 54 publications

References 35 publications

Disabled-2 Protein Facilitates Assembly Polypeptide-2-independent Recruitment of Cystic Fibrosis Transmembrane Conductance Regulator to Endocytic Vesicles in Polarized Human Airway Epithelial Cells

Disabled-2 Protein Facilitates Assembly Polypeptide-2-independent Recruitment of Cystic Fibrosis Transmembrane Conductance Regulator to Endocytic Vesicles in Polarized Human Airway Epithelial Cells

TheMYO6 interactome: selective motor‐cargo complexes for diverse cellular processes

Disabled‐2: A modular scaffold protein with multifaceted functions in signaling

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