Generation of ligand‐receptor alliances by “SEA” module‐mediated cleavage of membrane‐associated mucin proteins

Wreschner, Daniel H.; McGuckin, Michael A.; Williams, Stefanie J.; Baruch, Amos; Yoeli, Merav; Ziv, Ravit; Okun, Liron; Zaretsky, Joseph Z.; Smorodinsky, Nechama I.; Keydar, Iafa; Neophytou, Pavlos; Stacey, Martin; Lin, His-Hsien; Gordon, Siamon

doi:10.1110/ps.16502

Cited by 99 publications

(48 citation statements)

References 26 publications

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“…This processing has been implicated in cell-to-cell communication, apoptosis, signaling, sensing of chemical or mechanical stress, defense against infections and chemical damage, and cancer (37,43,44). Many of the above mentioned proteolytic events occur at SEA modules (37,42), and it was hypothesized that all membrane-residing proteins containing a SEA module will undergo cleavage as part of a regulatory mechanism based in receptor alliances (45).…”

Section: Discussionmentioning

confidence: 99%

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Structure of the Mature Ectodomain of the Human Receptor-type Protein-tyrosine Phosphatase IA-2

Primo

Klinke

Sica

et al. 2008

Journal of Biological Chemistry

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IA-2 (insulinoma-associated protein 2) is a protein-tyrosine phosphatase receptor located in secretory granules of neuroendocrine cells. Initially, it attracted attention due to its involvement in the autoimmune response associated to diabetes. Later it was found that upon exocytosis, the cytoplasmic domain of IA-2 is cleaved and relocated to the nucleus, where it enhances the transcription of the insulin gene. A concerted functioning of the whole receptor is to be expected. However, very little is known about the structure and function of the transmembrane and extracellular domains of IA-2. To address this issue, we solved the x-ray structure of the mature ectodomain of IA-2 (meIA-2) to 1.30 Å resolution. The fold of meIA-2 is related to the SEA (sea urchin sperm protein, enterokinase, agrin)) domains of mucins, suggesting its participation in adhesive contacts to the extracellular matrix and providing clues on how this kind of molecule may associate and form homo-and heterodimers. Moreover, we discovered that meIA-2 is self-proteolyzed in vitro by reactive oxygen species, suggesting the possibility of a new shedding mechanism that might be significant in normal function or pathological processes. Knowledge of meIA-2 structure should facilitate the search of its possible ligands and molecular interactions. Protein-tyrosine phosphatases (PTP),2 together with the corresponding kinases, regulate cell division, growth, differentiation, and metabolism (1). There are cytoplasmic PTP as well as transmembrane receptors PTP (RPTP). The latter also participate in cell-cell and cell-matrix contacts, possess an impressive diversity of adhesive and multimerization modules (2), and have been involved in human diseases such as cancer, autoimmunity, and degenerative processes (1).Two paralog RPTPs, IA-2 (insulinoma-associated protein 2, also termed PTP35 or ICA512) and IA-2 ␤ (PTPR2, also known as phogrin or IAR), were identified as major autoantigens in type-1 diabetes mellitus (3). They have a signal peptide, an ectodomain, a single-pass transmembrane region, and a single intracellular PTP domain.IA-2 and IA-2 ␤ are prominent in the secretory granules (SG) of brain, pituitary, pancreatic islet, and adrenal endocrine cells (4). Although the physiological ligands for these receptors are unknown and their function is poorly understood, they are involved in hormone and neuropeptide secretion. Indeed, single-and double-knock-out mice lacking IA-2 suffer from glucose intolerance, impaired insulin secretion, and abnormal secretion of pituitary hormones and female infertility (5, 6).Processing of pro IA-2 by furin-like hormone convertases produces mature IA-2 (7), which lacks the signal peptide and an adjacent fragment (residues 1-448). Mature IA-2 reaches the plasma membrane during exocytosis and comprises extracellular (449 -575), transmembrane (576 -600), and cytoplasmic domains (601-979). High glucose levels up-regulate IA-2 (8), and insulin exocytosis triggers a Ca 2ϩ -dependent and -calpain-mediated cleavage of the IA-2 cytopl...

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Section: Discussionmentioning

confidence: 99%

“…In some cases, shedding is due to specific membrane proteases (45). In other cases, autoproteolysis takes place.…”

Section: Discussionmentioning

confidence: 99%

Structure of the Mature Ectodomain of the Human Receptor-type Protein-tyrosine Phosphatase IA-2

Primo

Klinke

Sica

et al. 2008

Journal of Biological Chemistry

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“…The other TM mucin genes are dispersed through the genome. A number of structural characteristics are common to TM mucins: SEA domains that form cleavage sites have been identified in MUC1, MUC3A and MUC3B, MUC12, and MUC13 [15], whereas one or more epidermal growth factor-like domains are present in MUC3A, MUC3B, MUC4, MUC12, MUC13, and MUC17. Although the true role of TM mucins remains unclear, there is emerging evidence that they are involved in host defense from infection acting as both a physical barrier and by modulating epithelial growth and apoptosis via signal transduction.…”

Section: Introductionmentioning

confidence: 99%

The MUC13 cell surface mucin is highly expressed by human colorectal carcinomas

Walsh¹,

Young²,

Leggett³

et al. 2007

Human Pathology

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“…The X-ray structure of recombinant ME ICA512 (Fig. 1B) (18), encompassing amino acids 468 to 558, revealed that this region displays a ferredoxin-like fold related to the SEA (sea urchin sperm protein, enterokinase, agrin) domain, which is known to promote oligodimerization (24)(25)(26)(27)(28). Accordingly, both crystallized (18) and soluble (19) versions of ME ICA512 form dimers resulting from the antiparallel pairing of ␤2-␤2 or ␤4-␤4 strands ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Stability of proICA512/IA-2 and Its Targeting to Insulin Secretory Granules Require β4-Sheet-Mediated Dimerization of Its Ectodomain in the Endoplasmic Reticulum

Torkko

Primo

Dirkx

et al. 2015

Molecular and Cellular Biology

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fThe type 1 diabetes autoantigen ICA512/IA-2/RPTPN is a receptor protein tyrosine phosphatase of the insulin secretory granules (SGs) which regulates the size of granule stores, possibly via cleavage/signaling of its cytosolic tail. The role of its extracellular region remains unknown. Structural studies indicated that ␤2-or ␤4-strands in the mature ectodomain (ME ICA512) form dimers in vitro. Here we show that ME ICA512 prompts proICA512 dimerization in the endoplasmic reticulum. Perturbation of ME ICA512 ␤2-strand N-glycosylation upon S508A replacement allows for proICA512 dimerization, O-glycosylation, targeting to granules, and conversion, which are instead precluded upon G553D replacement in the ME ICA512 ␤4-strand. S508A/G553D and N506A/G553D double mutants dimerize but remain in the endoplasmic reticulum. Removal of the N-terminal fragment (ICA512-NTF) preceding ME ICA512 allows an ICA512-⌬NTF G553D mutant to exit the endoplasmic reticulum, and ICA512-⌬NTF is constitutively delivered to the cell surface. The signal for SG sorting is located within the NTF RESP18 homology domain (RESP18-HD), whereas soluble NTF is retained in the endoplasmic reticulum. Hence, we propose that the ME ICA512 ␤2-strand fosters proICA512 dimerization until NTF prevents N506 glycosylation. Removal of this constraint allows for proICA512 ␤4-strand-induced dimerization, exit from the endoplasmic reticulum, O-glycosylation, and RESP18-HD-mediated targeting to granules. R eceptor protein tyrosine phosphatases (RPTPs) form a large family of transmembrane proteins which counteract protein tyrosine kinases and are therefore involved in many signaling pathways. Dimerization of RPTPs is regarded as a main mechanism to regulate their constitutive intracellular phosphatase activity. The contributions of extracellular, transmembrane, and cytoplasmic PTP regions to dimerization vary among different RPTPs (1-4).The extracellular domains of RPTPs can promote receptor dimerization in several ways. As for receptor protein tyrosine kinases, RPTP oligomerization and clustering can be induced upon heterophilic binding to extracellular ligands. RPTPs for which such a mechanism has been demonstrated include the type I RPTP CD45/RPTPC, the type IIa protein RPTP, the type III protein RPTP␤, and the type V protein RPTP (5). In the case of CD45 and RPTP␤, changes in glycosylation pattern, including O-glycosylation, were shown to modulate their binding to galectin-1, conceivably increasing clustering and affecting phosphatase activity (6, 7). Homophilic interactions among ectodomains of RPTPs in the same or apposing cells, as is the case for the type IIb proteins RPTP and RPTP and the type IV protein RPTP␣, likely represent another mechanism for inducing receptor oligomerization and regulating phosphatase activity (8-10).The type VII RPTP ICA512/IA-2/PTPRN and its homologue phogrin/IA-2␤/PTPRN2 are "pseudophosphatases" with a large ectodomain followed by a transmembrane region and a single catalytically inactive PTP domain (11,12). They are expressed main...

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Generation of ligand‐receptor alliances by “SEA” module‐mediated cleavage of membrane‐associated mucin proteins

Cited by 99 publications

References 26 publications

Structure of the Mature Ectodomain of the Human Receptor-type Protein-tyrosine Phosphatase IA-2

Structure of the Mature Ectodomain of the Human Receptor-type Protein-tyrosine Phosphatase IA-2

The MUC13 cell surface mucin is highly expressed by human colorectal carcinomas

Stability of proICA512/IA-2 and Its Targeting to Insulin Secretory Granules Require β4-Sheet-Mediated Dimerization of Its Ectodomain in the Endoplasmic Reticulum

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