Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Combs, Michelle D.; Knutsen, Russell H.; Broekelmann, Thomas J.; Toennies, Holly M.; Brett, Thomas; Miller, Chantel A.; Kober, Daniel L.; Craft, Clarissa S.; Atkinson, Jeffrey J.; Shipley, J. Michael; Trask, Barbara Crippes; Mecham, Robert P.

doi:10.1074/jbc.m113.497727

Cited by 58 publications

(65 citation statements)

References 57 publications

(81 reference statements)

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“…Since elastin is critical for Windkessel function and structural integrity of the aortic wall [25], it is not surprising that loss of function of MAGP-2 is linked to aortic dilation in mice [26] and familiar thoracic aortic aneurisms in humans [27]. MAGP-2 may also serve other functions in the cardiovascular system since MAGP-2 contains an αvβ3 integrin binding RGD domain and has been shown to control angiogenesis [28] and vascular density in ovarian cancers [29].…”

Section: Direct Ecm-notch Interactions That Control Notch Signalingmentioning

confidence: 99%

Notch: A multi-functional integrating system of microenvironmental signals

LaFoya

Munroe

Mia

et al. 2016

Developmental Biology

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The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact with their microenvironmental neighbors through direct cell-cell interactions, thereby directing a variety of developmental processes. Recent research is discovering that Notch signaling is also responsive to a broad variety of stimuli beyond cell-cell interactions, including: ECM composition, crosstalk with other signaling systems, shear stress, hypoxia, and hyperglycemia. Given this emerging understanding of Notch responsiveness to microenvironmental conditions, it appears that the classical view of Notch as a mechanism enabling cell-cell interactions, is only a part of a broader function to integrate microenvironmental cues. In this review, we summarize and discuss published data supporting the idea that the full function of Notch signaling is to serve as an integrator of microenvironmental signals thus allowing cells to sense and respond to a multitude of conditions around them.

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Section: Direct Ecm-notch Interactions That Control Notch Signalingmentioning

confidence: 99%

Notch: A multi-functional integrating system of microenvironmental signals

LaFoya

Munroe

Mia

et al. 2016

Developmental Biology

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“…The biological relevance of two MAGP-1 binding sites on fibrillin is not understood, nor is it known whether both sites are occupied at the same time. MAGP-1 is not required for fibrillin assembly or for stabilizing lateral interactions of fibrillin molecules, since microfibrils form normally without MAGP-1 or MAGP-2 [69]. …”

Section: Magp-1mentioning

confidence: 99%

The microfibril-associated glycoproteins (MAGPs) and the microfibrillar niche

Mecham

Gibson

2015

Matrix Biology

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The microfibril-associated glycoproteins MAGP-1 and MAGP-2 are extracellular matrix proteins that interact with fibrillin to influence microfibril function. The two proteins are related through a 60 amino acid matrix-binding domain but their sequences differ outside of this region. A distinguishing feature of both proteins is their ability to interact with TGFβ family growth factors, Notch and Notch ligands, and multiple elastic fiber proteins. MAGP-2 can also interact with αvβ3 integrins via an RGD sequence that is not found in MAGP-1. Morpholino knockdown of MAGP-1 expression in zebrafish results in abnormal vessel wall architecture and altered vascular network formation. In the mouse, MAGP-1 deficiency had little effect on elastic fibers in blood vessels and lung but resulted in numerous unexpected phenotypes including bone abnormalities, hematopoietic changes, increased fat deposition, diabetes, impaired wound repair, and a bleeding diathesis. Inactivation of the gene for MAGP-2 in mice produced a neutropenia yet had minimal effects on bone or adipose homeostasis. Double knockouts had phenotypes characteristic of each individual knockout as well as several additional traits only seen when both genes are inactivated. A common mechanism underlying all of the traits associated with the knockout phenotypes is altered TGFβ signaling. This review summarizes our current understanding of the function of the MAGPs and discusses ideas related to their role in growth factor regulation.

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“…17,18 A growth-factor binding domain has been identified near the Nterminus of MAGP1 that has high affinity for members of the TGFb superfamily (Fig. 1A).…”

Section: Magp1 and Growth Factor Regulationmentioning

confidence: 99%

MAGP1, the extracellular matrix, and metabolism

Craft¹

2014

Adipocyte

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Adipose tissue and the extracellular matrix were once considered passive players in regulating physiological processes. Now, both entities are acknowledged for their capacity to engage signal transduction pathways, and for their involvement in maintaining normal tissue homeostasis. We recently published a series of studies that identified a novel mechanism whereby an extracellular matrix molecule, MAGP1 (microfibril associated glycoprotein 1), can regulate energy metabolism in adipose tissue. MAGP1 is a component of extracellular microfibrils and plays a supportive role in maintaining thermoregulation by indirectly regulating expression of the thermogenic uncoupling proteins (UCPs). The focus of this commentary is to draw attention to the role of the extracellular matrix in regulating the bioavailability of signaling molecules, like transforming growth factor β (TGFβ), and exemplify that a better understanding of the extracellular matrix's biological properties could unveil a new source of therapeutic targets for metabolic diseases.

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Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Abstract: Background:The function of MAGP2 was studied by inactivating its gene (Mfap5 Ϫ/Ϫ ) in mice.

Cited by 58 publications

References 57 publications

Notch: A multi-functional integrating system of microenvironmental signals

Notch: A multi-functional integrating system of microenvironmental signals

The microfibril-associated glycoproteins (MAGPs) and the microfibrillar niche

MAGP1, the extracellular matrix, and metabolism

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