Myosin VI and its cargo adaptors – linking endocytosis and autophagy

Tumbarello, David A.; Kendrick‐Jones, John; Buß, Folma

doi:10.1242/jcs.095554

Cited by 117 publications

(136 citation statements)

References 104 publications

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“…Increasing evidence suggests that RTKs and other signaling proteins can also be regulated and degraded through selective autophagy, including EGFR (37), FLT3 (38), GLUT1 (39), and Src (40). Synectin shares the same myosin VI binding site as target of Myb1 membrane trafficking protein 1 (TOM1), a known autophagy mediator, thus supporting the premise that synectin can regulate the autophagic fate of specific proteins (41). Despite this premise, there is limited data demonstrating this level of action of a scaffold protein such as synectin.…”

Section: Discussionmentioning

confidence: 92%

Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms

Drinane¹,

Yaqoob²,

Yu³

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 92%

Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms

Drinane¹,

Yaqoob²,

Yu³

et al. 2017

JCI Insight

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“…It has diverse functional roles including endocytosis, in which it is recruited to clathrin coated vesicles through its globular tail domain (Fig. 1) by Dab2, and secretion, in which it is recruited to the Golgi through its globular tail domain via optineurin, and autophagy [75]. MYO6 can also bind to phosphoinositides [76].…”

Section: Class 5 6 10 and 19 Myosin Isoformsmentioning

confidence: 99%

How myosin organization of the actin cytoskeleton contributes to the cancer phenotype

Peckham

2016

Biochemical Society Transactions

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The human genome contains 39 genes that encode myosin heavy chains, classified on the basis of their sequence similarity into 12 classes. Most cells express at least 12 different genes, from at least 8 different classes, which are typically composed of several class 1 genes, at least one class 2 gene, and classes 5, 6, 9, 10, 18 and 19. While the different myosin isoforms all have specific and non-overlapping roles in the cell, in combination they all contribute to the organisation of the actin cytoskeleton, and the shape and phenotype of the cell. Over (or under) expression of these different myosin isoforms can have strong effects on actin organisation, cell shape, and contribute to the cancer phenotype as discussed in this review.

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“…Uniquely among myosin motors, it takes these steps toward the minus end of actin filaments (3). In cells and tissues, MYO6 has been implicated in an ever-growing list of functions, including secretion, endocytosis, cell migration, stereocilia maintenance, and autophagy (4). It mediates these functions through interactions with a wide array of cargo adaptor proteins that bind to the tail region of MYO6, thereby localizing and potentially activating the motor through conformational change and unfolding of the lever arm (5) mediated by calcium (6).…”

mentioning

confidence: 99%

Filopodia formation and endosome clustering induced by mutant plus-end–directed myosin VI

Masters

Buß

2017

Proc. Natl. Acad. Sci. U.S.A.

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Myosin VI (MYO6) is the only myosin known to move toward the minus end of actin filaments. It has roles in numerous cellular processes, including maintenance of stereocilia structure, endocytosis, and autophagosome maturation. However, the functional necessity of minus-end-directed movement along actin is unclear as the underlying architecture of the local actin network is often unknown. To address this question, we engineered a mutant of MYO6, MYO6+, which undergoes plus-end-directed movement while retaining physiological cargo interactions in the tail. Expression of this mutant motor in HeLa cells led to a dramatic reorganization of cortical actin filaments and the formation of actin-rich filopodia. MYO6 is present on peripheral adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) signaling endosomes and MYO6+ expression causes a dramatic relocalization and clustering of this endocytic compartment in the cell cortex. MYO6+ and its adaptor GAIP interacting protein, C terminus (GIPC) accumulate at the tips of these filopodia, while APPL1 endosomes accumulate at the base. A combination of MYO6+ mutagenesis and siRNA-mediated depletion of MYO6 binding partners demonstrates that motor activity and binding to endosomal membranes mediated by GIPC and PI(4,5)P 2 are crucial for filopodia formation. A similar reorganization of actin is induced by a constitutive dimer of MYO6+, indicating that multimerization of MYO6 on endosomes through binding to GIPC is required for this cellular activity and regulation of actin network structure. This unique engineered MYO6+ offers insights into both filopodia formation and MYO6 motor function at endosomes and at the plasma membrane.is a monomeric motor protein with a large working stroke (1), which takes processive 36-nm steps along actin filaments in vitro when dimerized (2). Uniquely among myosin motors, it takes these steps toward the minus end of actin filaments (3). In cells and tissues, MYO6 has been implicated in an ever-growing list of functions, including secretion, endocytosis, cell migration, stereocilia maintenance, and autophagy (4). It mediates these functions through interactions with a wide array of cargo adaptor proteins that bind to the tail region of MYO6, thereby localizing and potentially activating the motor through conformational change and unfolding of the lever arm (5) mediated by calcium (6). However, how the mechanical properties (for instance step size, duty ratio, stall force, etc.) and in particular the directionality of MYO6 relate to its biological roles is poorly understood.Isolated, purified MYO6 is primarily monomeric (1), but can dimerize in vitro through interactions between the cargo binding domain and adaptor molecules (2, 7). Whether any of these adaptors are capable of inducing functional MYO6 dimers in cells is not known and there has been little definitive evidence as to whether MYO6 functions as a monomer or as a processive dimer in cells and how motor processivity relates to its biological function (8,...

show abstract

Myosin VI and its cargo adaptors – linking endocytosis and autophagy

Cited by 117 publications

References 104 publications

Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms

Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms

How myosin organization of the actin cytoskeleton contributes to the cancer phenotype

Filopodia formation and endosome clustering induced by mutant plus-end–directed myosin VI

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