Localized signals that regulate transendothelial migration

Müller, William A.

doi:10.1016/j.coi.2015.10.006

Cited by 49 publications

(54 citation statements)

References 55 publications

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“…Using a proteomics screen, we recently identified cell adhesion molecule CD99 as a putative meprin-b substrate (9). CD99 was shown to be essential for proper TEM of certain immune cells, thus being essential for the inflammatory response (16). However, the mechanism of how the CD99 homophilic interaction between the endothelial and infiltrating cell dissociates during diapedesis is ambiguous (17).…”

Section: Discussionmentioning

confidence: 99%

“…It has also been shown that meprin b exhibits proinflammatory activity and cleavage of factors such as IL-1b, -18, and -6 (13)(14)(15). Inflammation is a tightly controlled cellular process mainly regulated by cell adhesion molecules (16,17).…”

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confidence: 99%

“…Inflammation is a tightly controlled cellular process mainly regulated by cell adhesion molecules (16,17).…”

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confidence: 99%

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Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration

et al. 2016

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ABSTRACT:The adhesion molecule CD99 is essential for the transendothelial migration of leukocytes. In this study, we used biochemical and cellular assays to show that CD99 undergoes ectodomain shedding by the metalloprotease meprin b and subsequent intramembrane proteolysis by g-secretase. The cleavage site in CD99 was identified by mass spectrometry within an acidic region highly conserved through different vertebrate species. This finding fits perfectly to the unique cleavage specificity of meprin b with a strong preference for aspartate residues and suggests coevolution of protease and substrate. We hypothesized that limited CD99 cleavage by meprin b would alter cellular transendothelial migration (TEM) behavior in tissue remodeling processes, such as inflammation and cancer. Indeed, meprin b induced cell migration of Lewis lung carcinoma cells in an in vitro TEM assay. Accordingly, deficiency of meprin b in Mep1b 2/2 mice resulted in significantly increased CD99 protein levels in the lung. Therefore, meprin b could serve as a therapeutic target, given that in a proof-of-concept approach we showed accumulation of CD99 protein in lungs of meprin b inhibitortreated mice.-Bedau, T., Peters, F., Prox, J., Arnold, P., Schmidt, F., Finkernagel, M., Köllmann, S., Wichert, R., Otte, A., Ohler, A., Stirnberg, M., Lucius, R., Koudelka, T., Tholey, A., Biasin, V., Pietrzik, C. U., Kwapiszewska, G., Becker-Pauly, C. Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin b and promotes transendothelial cell migration. FASEB J. 31, 1226-1237 (2017). www.fasebj.orgRegulated intramembrane proteolysis (RIP) of cell adhesion molecules, such as junctional adhesion molecule (JAM)-A, intercellular adhesion molecule (ICAM)-1, and L-selectin, was shown to be essential for transendothelial migration (TEM) of inflammatory or cancer cells (1). Meprin b, a multidomain type I transmembrane metalloprotease, is an initiator of RIP, and structural studies revealed dimeric formation of the protease with the active site in proximity to the cell surface (2-4). In addition, meprin b can be shed from the cell surface by ADAM10/ 17, resulting in a soluble active protease, which for instance is important for mucus detachment in the small intestine (5). Meprin b is characterized by a unique cleavage specificity, with a preference for negatively charged amino acids (6). These structural features provide all requirements that meprin b must have to act as an ectodomain sheddase at the cell surface. Indeed, membrane-bound amyloid precursor protein (APP), for instance, is cleaved by meprin b, resulting in the release of sAPP-b fragments and neurotoxic Ab peptides (4,7,8). Many of the known substrates of meprin b have been identified by mass spectrometry (MS)-based proteomic approaches (9).

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Section: Discussionmentioning

confidence: 99%

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Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration

et al. 2016

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“…However, when improperly regulated, whether overstimulated (reperfusion injury) or self-directed (arthritis [Firestein and McInnes, 2017] and multiple sclerosis [Grigoriadis et al, 2015]), uncontrolled inflammation becomes pathological. One of the critical steps in mounting an effective inflammatory response is the recruitment of various leukocytes to the site of inflammation, and thus, this represents an attractive therapeutic target to reduce untoward inflammation (Muller, 2016a,b).…”

Section: Introductionmentioning

confidence: 99%

Endothelial IQGAP1 regulates leukocyte transmigration by directing the LBRC to the site of diapedesis

Sullivan

Dalal

Jaulin

et al. 2019

Journal of Experimental Medicine

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Transendothelial migration (TEM) of leukocytes across the endothelium is critical for inflammation. In the endothelium, TEM requires the coordination of membrane movements and cytoskeletal interactions, including, prominently, recruitment of the lateral border recycling compartment (LBRC). The scaffold protein IQGAP1 was recently identified in a screen for LBRC-interacting proteins. Knockdown of endothelial IQGAP1 disrupted the directed movement of the LBRC and substantially reduced leukocyte TEM. Expression of truncated IQGAP1 constructs demonstrated that the calponin homology domain is required for IQGAP1 localization to endothelial borders and that the IQ domain, on the same IQGAP1 polypeptide, is required for its function in TEM. This is the first reported function of IQGAP1 requiring two domains to be present on the same polypeptide. Additionally, we show for the first time that IQGAP1 in the endothelium is required for efficient TEM in vivo. These findings reveal a novel function for IQGAP1 and demonstrate that IQGAP1 in endothelial cells facilitates TEM by directing the LBRC to the site of TEM.

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“…In most tissues the leukocyte response to inflammatory stimuli takes place in postcapillary venules (1). Leukocytes and endothelial cells undergo a coordinated and stereotyped series of increasingly tight adhesive interactions designed to capture leukocytes from the bloodstream (2)(3)(4)(5).…”

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How monocytes guard the glomerulus

Müller¹

2016

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

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Localized signals that regulate transendothelial migration

Cited by 49 publications

References 55 publications

Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration

Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration

Endothelial IQGAP1 regulates leukocyte transmigration by directing the LBRC to the site of diapedesis

How monocytes guard the glomerulus

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