Antibody-Induced Shedding of CD44 from Adherent Cells Is Linked to the Assembly of the Cytoskeleton

Shi, Mei; Dennis, Kathryn; Peschon, Jacques J.; Chandrasekaran, Raman; Mikecz, Katalin

doi:10.4049/jimmunol.167.1.123

Cited by 55 publications

(55 citation statements)

References 55 publications

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“…4D). Shedding independent of TACE/ADAM17 was also reported for CD44 (8), an adhesion molecule with some similarities in structure and function to CD93 (29). One consequence of ectodomain cleavage is the subsequent regulated cleavage of the transmembrane domain, resulting in the liberation of the ICD into the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

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CD93 Is Rapidly Shed from the Surface of Human Myeloid Cells and the Soluble Form Is Detected in Human Plasma

Bohlson

Silva

Fonseca

et al. 2005

The Journal of Immunology

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CD93 is a highly glycosylated transmembrane protein expressed on monocytes, neutrophils, endothelial cells, and stem cells. Antibodies directed at CD93 modulate phagocytosis, and CD93-deficient mice are defective in the clearance of apoptotic cells from the inflamed peritoneum. In this study we observe that CD93, expressed on human monocytes and neutrophils, is susceptible to phorbol dibutyrate-induced protein ectodomain shedding in a time- and dose-dependent manner. The soluble fragment found in culture supernatant retains the N-terminal carbohydrate recognition domain and the epidermal growth factor repeats after ectodomain cleavage. Importantly, a soluble form of the CD93 ectodomain was detected in human plasma, demonstrating that shedding is a physiologically relevant process. Inhibition of metalloproteinases with 1,10-phenanthroline inhibited shedding, but shedding was independent of TNF-α-converting enzyme (a disintegrin and metalloproteinase 17). Phorbol dibutyrate-induced CD93 shedding on monocytes was accompanied by decreased surface expression, whereas neutrophils displayed an increase in surface expression, suggesting that CD93 shed from the neutrophil surface was rapidly replaced by CD93 from intracellular stores. Cross-linking CD93 on human monocytes with immobilized anti-CD93 mAbs triggered shedding, as demonstrated by a decrease in cell-associated, full-length CD93 concomitant with an increase in CD93 intracellular domain-containing cleavage products. In addition, the inflammatory mediators, TNF-α and LPS, stimulated ectodomain cleavage of CD93 from monocytes. These data demonstrate that CD93 is susceptible to ectodomain shedding, identify multiple stimuli that trigger shedding, and identify both a soluble form of CD93 in human plasma and intracellular domain containing cleavage products within cells that may contribute to the physiologic role of CD93.

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Section: Discussionmentioning

confidence: 99%

“…The majority of mice made deficient in TACE die between embryonic day 17.5 and the first day after birth, illustrating the importance of ectodomain shedding in mammalian development (7). However, TACE is not a universal sheddase, because a variety of transmembrane proteins, including CD44, are cleaved by distinct metalloproteinases (8).…”

mentioning

confidence: 99%

CD93 Is Rapidly Shed from the Surface of Human Myeloid Cells and the Soluble Form Is Detected in Human Plasma

Bohlson

Silva

Fonseca

et al. 2005

The Journal of Immunology

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“…As shown in Fig. 4A, the addition of MIA PaCa-2 culture supernatant induced the up-regulation of CD44 cleavage in MIA PaCa-2 cells, as evidenced by an increase in the membrane-bound 25-kDa cleavage product in Western blotting analysis; this cleavage was strongly inhibited by the Fab fragment of the anti-CD44 neutralizing monoclonal antibody BRIC235 (29,43), indicating that the up-regulated CD44 cleavage was because of the interaction between CD44 and its ligand. Furthermore, as shown in Fig.…”

Section: Mia Paca-2 Cells Express Hyaluronidases and Secrete Them Intmentioning

confidence: 96%

Tumor Cells Enhance Their Own CD44 Cleavage and Motility by Generating Hyaluronan Fragments

Sugahara

Hirata

Hayasaka

et al. 2006

Journal of Biological Chemistry

128

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Hyaluronan (HA) is an extracellular matrix glycosaminoglycan that interacts with cell-surface receptors, including CD44. Although HA usually exists as a high molecular mass polymer, HA of a much lower molecular mass that shows a variety of biological activities can be detected under certain pathological conditions, particularly in tumors. We previously reported that low molecular weight HAs (LMW-HAs) of a certain size range induce the proteolytic cleavage of CD44 from the surface of tumor cells and promote tumor cell migration in a CD44-dependent manner. Here, we show that MIA PaCa-2, a human pancreatic carcinoma cell line, secreted hyaluronidases abundantly and generated readily detectable levels of LMW-HAs ranging from ϳ10-to 40-mers. This occurred in the absence of any exogenous stimulation. The tumor-derived HA oligosaccharides were able to enhance CD44 cleavage and tumor cell motility. Inhibition of the CD44-HA interaction resulted in the complete abrogation of these cellular events. These results are consistent with the concept that tumor cells generate HA oligosaccharides that bind to tumor cell CD44 through the expression of their own constitutive hyaluronidases. This enhances their own CD44 cleavage and cell motility, which would subsequently promote tumor progression. Such an autocrine/paracrine-like process may represent a novel activation mechanism that would facilitate and promote the malignant potential of tumor cells.Hyaluronan (HA), 2 one of the major components of the extracellular matrix, is a high molecular weight linear glycosaminoglycan consisting of repeating disaccharide units of D-glucuronic acid and N-acetyl-Dglucosamine, whose molecular size can reach 10 7 kDa (1, 2). Despite its simple composition, HA possesses a number of functions. It influences the hydration and physical properties of tissues (1, 3), interacts with other extracellular matrix macromolecules such as aggrecan (4) and versican (5), and interacts with cell-surface receptors, notably CD44 (6). Through these functions, HA forms a pericellular coat around cells (2, 7) and participates in physiological events such as cell adhesion, migration, and proliferation (8). It is also involved in pathological conditions, including cancer (7). An increased synthesis of HA has been reported in various malignant tumors such as breast and ovarian carcinomas, and predicts a poor prognosis (9, 10). HA enhances tumor cell adhesion and migration (11) and influences several signaling pathways, including some that promote tumor cell growth and survival, such as ErbB2, Ras, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/ Akt (12-14).Hyaluronidases play critical roles in HA metabolism (15). Six human hyaluronidase-like sequences are present in the human genome. These are HYAL1, HYAL2, HYAL3, HYAL4, SPAM1, and PHYAL1, which, respectively, encode Hyal-1, Hyal-2, Hyal-3, Hyal-4, PH-20, and a pseudogene that is transcribed but not translated (16). Of these hyaluronidases, only Hyal-1 and Hyal-2 have been characterized well. Hyal...

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“…CD44ICD is transported to the nucleus and activates transcription. Cleavage of CD44 is triggered by extracellular Ca 2+ influx, and the activation of PKC and Rho GTPases (Okamoto et al, 1999;Shi et al, 2001). These factors are indeed triggered by the mechanical stretch (Nagano and Saya, 2004).…”

Section: Cellular Mechanotransductionmentioning

confidence: 99%

Mechanoregulation of gene expression in fibroblasts

Wang

Thampatty

Lin

et al. 2007

Gene

227

187

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Mechanical loads placed on connective tissues alter gene expression in fibroblasts through mechanotransduction mechanisms by which cells convert mechanical signals into cellular biological events, such as gene expression of extracellular matrix components (e.g., collagen). This mechanical regulation of ECM gene expression affords maintenance of connective tissue homeostasis. However, mechanical loads can also interfere with homeostatic cellular gene expression and consequently cause the pathogenesis of connective tissue diseases such as tendinopathy and osteoarthritis. Therefore, the regulation of gene expression by mechanical loads is closely related to connective tissue physiology and pathology. This article reviews the effects of various mechanical loading conditions on gene regulation in fibroblasts and discusses several mechanotransduction mechanisms. Future research directions in mechanoregulation of gene expression are also suggested.

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Antibody-Induced Shedding of CD44 from Adherent Cells Is Linked to the Assembly of the Cytoskeleton

Cited by 55 publications

References 55 publications

CD93 Is Rapidly Shed from the Surface of Human Myeloid Cells and the Soluble Form Is Detected in Human Plasma

CD93 Is Rapidly Shed from the Surface of Human Myeloid Cells and the Soluble Form Is Detected in Human Plasma

Tumor Cells Enhance Their Own CD44 Cleavage and Motility by Generating Hyaluronan Fragments

Mechanoregulation of gene expression in fibroblasts

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