The clathrin adaptor Dab2 recruits EH domain scaffold proteins to regulate integrin β1 endocytosis

Teckchandani, Anjali; Mulkearns, Erin E.; Randolph, Timothy W.; Toida, Natalie; Cooper, Jonathan A.

doi:10.1091/mbc.e11-12-1007

Cited by 56 publications

(87 citation statements)

References 51 publications

(97 reference statements)

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“…RNAi of ARH had a weaker effect, whereas suppression of Numb showed no significant inhibition. Our data agree well with previous studies (Chao and Kunz, 2009;Teckchandani et al, 2012) showing that Dab2 strongly inhibits the internalization of b1 integrin when downregulated. Furthermore, surface levels of integrins b1 and a2 increase in Dab2-deficient HeLa cells (Teckchandani et al, 2009).…”

Section: Kif15 Is Required For Cell-surface Localization Of Dab2supporting

confidence: 93%

“…It has been shown that several CLASPs (alternative clathrin adaptors) are required for integrin internalization (Nishimura and Kaibuchi, 2007;Teckchandani et al, 2009). By contrast, internalization of the transferrin receptor is not dependent upon CLASPs such as Dab2 (Teckchandani et al, 2009;Teckchandani et al, 2012;Maurer and Cooper, 2006;Keyel et al, 2006). In our experiments, RNAi of Dab2, ARH and Numb for 48 h caused .80% reduction in the level of the respective transcripts (Fig.…”

Section: Kif15 Is Required For Cell-surface Localization Of Dab2mentioning

confidence: 46%

“…Depletion of Numb, the adaptor with a preference for a5 integrin (Teckchandani et al, 2009), resulted in no significant change in the intracellular accumulation of a2 integrin. As Dab2 is known to inhibit the internalization of unbound b1 integrin (Teckchandani et al, 2009;Teckchandani et al, 2012) and appeared to be the strongest effector of the intracellular accumulation of non-clustered a2 integrin, we focused on Dab2 for further analysis. We could show that the downregulation of KIF15 induced redistribution of punctate Dab2 structures from the plasma membrane (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, the transferrin distribution might be affected by the mislocalized Dab2, which was shown to regulate the recycling of numerous proteins, including transferrin (Fu et al, 2012). As Dab2-mediated internalization of integrins occurs through the clathrin-dependent pathway (Teckchandani et al, 2012;Ezratty et al, 2009;Chao and Kunz, 2009), KIF15 might contribute to the regulation of the endocytic fate of a2 integrin. Whether KIF15 influences Dab2 distribution through direct binding, as demonstrated for the actin-based molecular motor myosin 6 (Spudich et al, 2007;Morris et al, 2002), or indirectly remains to be answered, particularly within the context of cell cycle progression, as Dab2 cell-surface localization and function in endocytosis change throughout the cell cycle (Chetrit et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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RNAi screen identifies KIF15 as a novel regulator of integrin endocytic trafficking

Eskova

Knapp

Matelska

et al. 2014

Journal of Cell Science

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ABSTRACTa2b1 integrin is one of the most important collagen-binding receptors, and it has been implicated in numerous thrombotic and immune diseases. a2b1 integrin is a potent tumour suppressor, and its downregulation is associated with increased metastasis and poor prognosis in breast cancer. Currently, very little is known about the mechanism that regulates the cell-surface expression and trafficking of a2b1 integrin. Here, using a quantitative fluorescence-microscopybased RNAi assay, we investigated the impact of 386 cytoskeletonassociated or -regulatory genes on a2 integrin endocytosis and found that 122 of these affected the intracellular accumulation of a2 integrin. Of these, 83 were found to be putative regulators of a2 integrin trafficking and/or expression, with no observed effect on the internalization of epidermal growth factor (EGF) or transferrin. Further interrogation and validation of the siRNA screen revealed a role for KIF15, a microtubule-based molecular motor, as a significant inhibitor of the endocytic trafficking of a2 integrin. Our data suggest a novel role for KIF15 in mediating plasma membrane localization of the alternative clathrin adaptor Dab2, thus impinging on pathways that regulate a2 integrin internalization.

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Section: Kif15 Is Required For Cell-surface Localization Of Dab2supporting

confidence: 93%

Section: Kif15 Is Required For Cell-surface Localization Of Dab2mentioning

confidence: 46%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

RNAi screen identifies KIF15 as a novel regulator of integrin endocytic trafficking

Eskova

Knapp

Matelska

et al. 2014

Journal of Cell Science

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“…Indeed, the EH domains bind proteins targets containing Asp-Pro-Phe (NPF) motifs including endocytic components such as Epsin, Dab2, Numb, and Stonin2, among others [4–6]. The CC domains promote homo- and heterodimerization of ITSNs [7] as well as interaction with proteins from the endocytic (e.g.…”

Section: Structure and Subcellular Localizationmentioning

confidence: 99%

Intersectin scaffold proteins and their role in cell signaling and endocytosis

Herrero-Garcia

O’Bryan

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Intersectins (ITSNs) are a family of multi-domain proteins involved in regulation of diverse cellular pathways. These scaffold proteins are well known for regulating endocytosis but also play important roles in cell signaling pathways including kinase regulation and Ras activation. ITSNs participate in several human cancers, such as neuroblastomas and glioblastomas, while its downregulation is associated with lung injury. Alterations in ITSN expression have been found in neurodegenerative diseases such as Down Syndrome and Alzheimer’s disease. Binding proteins for ITSNs include endocytic regulatory factors, cytoskeleton related proteins (i.e. actin or dynamin), signaling proteins as well as herpes virus proteins. This review will summarize recent studies on ITSNs, highlighting the importance of these scaffold proteins in the aforementioned processes.

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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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The clathrin adaptor Dab2 recruits EH domain scaffold proteins to regulate integrin β1 endocytosis

Cited by 56 publications

References 51 publications

RNAi screen identifies KIF15 as a novel regulator of integrin endocytic trafficking

RNAi screen identifies KIF15 as a novel regulator of integrin endocytic trafficking

Intersectin scaffold proteins and their role in cell signaling and endocytosis

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

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