The family of fibroblast growth factors (FGFs) regulates a plethora of developmental processes, including brain patterning, branching morphogenesis and limb development. Several mitogenic, cytoprotective and angiogenic therapeutic applications of FGFs are already being explored, and the recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in bile acid, glucose and phosphate homeostasis has sparked renewed interest in the pharmacological potential of this family. This Review discusses traditional applications of recombinant FGFs and small-molecule FGF receptor kinase inhibitors in the treatment of cancer and cardiovascular disease and their emerging potential in the treatment of metabolic syndrome and hypophosphataemic diseases.

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The FGF family: biology, pathophysiology and therapy.

Glycosylation is the most abundant and diverse posttranslational modification of proteins. While several types of glycosylation can be predicted by the protein sequence context, and substantial knowledge of these glycoproteomes is available, our knowledge of the GalNAc‐type O ‐glycosylation is highly limited. This type of glycosylation is unique in being regulated by 20 polypeptide GalNAc‐transferases attaching the initiating GalNAc monosaccharides to Ser and Thr (and likely some Tyr) residues. We have developed a genetic engineering approach using human cell lines to simplify O ‐glycosylation (SimpleCells) that enables proteome‐wide discovery of O ‐glycan sites using ‘bottom‐up’ ETD‐based mass spectrometric analysis. We implemented this on 12 human cell lines from different organs, and present a first map of the human O ‐glycoproteome with almost 3000 glycosites in over 600 O ‐glycoproteins as well as an improved NetOGlyc4.0 model for prediction of O ‐glycosylation. The finding of unique subsets of O ‐glycoproteins in each cell line provides evidence that the O ‐glycoproteome is differentially regulated and dynamic. The greatly expanded view of the O ‐glycoproteome should facilitate the exploration of how site‐specific O ‐glycosylation regulates protein function.

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Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology

Glycosylation of proteins is an essential process in all eukaryotes and a great diversity in types of protein glycosylation exists in animals, plants and microorganisms. Mucin-type O-glycosylation, consisting of glycans attached via O-linked N-acetylgalactosamine (GalNAc) to serine and threonine residues, is one of the most abundant forms of protein glycosylation in animals. Although most protein glycosylation is controlled by one or two genes encoding the enzymes responsible for the initiation of glycosylation, i.e. the step where the first glycan is attached to the relevant amino acid residue in the protein, mucin-type O-glycosylation is controlled by a large family of up to 20 homologous genes encoding UDP-GalNAc:polypeptide GalNAc-transferases (GalNAc-Ts) (EC 2.4.1.41). Therefore, mucin-type O-glycosylation has the greatest potential for differential regulation in cells and tissues. The GalNAc-T family is the largest glycosyltransferase enzyme family covering a single known glycosidic linkage and it is highly conserved throughout animal evolution, although absent in bacteria, yeast and plants. Emerging studies have shown that the large number of genes (GALNTs) in the GalNAc-T family do not provide full functional redundancy and single GalNAc-T genes have been shown to be important in both animals and human. Here, we present an overview of the GalNAc-T gene family in animals and propose a classification of the genes into subfamilies, which appear to be conserved in evolution structurally as well as functionally.

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Control of mucin-type O-glycosylation: A classification of the polypeptide GalNAc-transferase gene family

In contrast to the regulation of calcium homeostasis, which has been extensively studied over the past several decades, relatively little is known about the regulation of phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by PTH, 1,25(OH)2-vitamin D (1,25(OH)2D), dietary and serum phosphorus levels. Synthesis and secretion of FGF23 by osteocytes are positively regulated by 1,25(OH)2D and serum phosphorus and negatively regulated, through yet unknown mechanisms, by the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and by dentin matrix protein 1 (DMP1). In turn, FGF23 inhibits the synthesis of 1,25(OH)2D, and it may negatively regulate the secretion of parathyroid hormone (PTH) from the parathyroid glands. However, FGF23 synergizes with PTH to increase renal phosphate excretion by reducing expression of the renal sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc...

Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23.

Calcium (Ca2+) and phosphate (PO43−) homeostasis are coordinated by systemic and local factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and reabsorption of these ions through a complex hormonal network. Traditionally, the parathyroid hormone (PTH)/vitamin D axis provided the conceptual framework to understand mineral metabolism. PTH secreted by the parathyroid gland in response to hypocalcemia functions to maintain serum Ca2+ levels by increasing Ca2+ reabsorption and 1,25-dihydroxyvitamin D [1,25(OH)2D] production by the kidney, enhancing Ca2+ and PO43− intestinal absorption and increasing Ca2+ and PO43− efflux from bone, while maintaining neutral phosphate balance through phosphaturic effects. FGF23 is a recently discovered hormone, predominately produced by osteoblasts/osteocytes, whose major functions are to inhibit renal tubular phosphate reabsorption and suppress circulating 1,25(OH)2D levels by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25(OH)2D. FGF23 participates in a new bone/kidney axis that protects the organism from excess vitamin D and coordinates renal PO43− handling with bone mineralization/turnover. Abnormalities of FGF23 production underlie many inherited and acquired disorders of phosphate homeostasis. This review discusses the known and emerging functions of FGF23, its regulation in response to systemic and local signals, as well as the implications of FGF23 in different pathological and physiological contexts.

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Regulation and Function of the FGF23/Klotho Endocrine Pathways

Familial tumoral calcinosis (FTC; OMIM 211900) is a severe autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Using linkage analysis, we mapped the gene underlying FTC to 2q24-q31. This region includes the gene GALNT3, which encodes a glycosyltransferase responsible for initiating mucin-type O-glycosylation. Sequence analysis of GALNT3 identified biallelic deleterious mutations in all individuals with FTC, suggesting that defective post-translational modification underlies the disease.

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Mutations in GALNT3 , encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis

PURPOSE. This study is designed to provide a comprehensive expression profile of connexins in the human corneal epithelium (in vivo) and in cultured primary corneal epithelial cells (PCECs) (in vitro). It also evaluates the pathologic effects of a pathogenic missense mutation in Cx26, which causes keratitisichthyosis-deafness syndrome (KIDS), a rare genetic disorder with corneal involvement. METHODS. RT-PCR analysis, immunohistochemistry, and fluorescent dye transfer assays were used to determine the expression pattern and gap junction intercellular communication in PCECs and human cornea. Differentiation-dependent differences in connexin expression of PCECs after a calcium switch were verified by real-time RT-PCR. The common KIDS mutation Cx26(D50N) was studied by determining transient expression in PCECs. RESULTS. In vivo immunostaining revealed widespread and overlapping expression of Cx43 and -30 in the basal and suprabasal layers. Cx26 staining was limited to the lower suprabasal cells, whereas Cx31.1 localized to the apical surface of basal cells in the central cornea and to the lower and middle suprabasal cells in the limbal region. Immunostaining for nine other connexins, including Cx50, was negative. In PCEC, nine connexin genes were detectable by RT-PCR, however, only Cx26, -30, and -43 formed visible gap junction plaques. HighCa 2 culture conditions were accompanied by a 1.6- to 2.2-fold upregulation of expression of Cx26, -30, and -43 and a significant increase in gap-junction‐mediated dye transfer. Transient expression of mutant Cx26(D50N) in PCECs resulted in cytoplasmic accumulation and lack of gap junction plaque formation and was not altered by coexpression of wild-type (wt)Cx26 or -30. CONCLUSIONS. Gap junction communication in the human corneal epithelium is mediated by Cx26, -30, -31.1, and -43. Poorly differentiated PCECs are uncoupled, and Ca 2 induced differentiation is associated with an upregulation of connexin expression and intercellular communication. The transfection experiments suggest that KIDS Cx26(D50N) impairs intracellular formation and transport of connexons formed by Cx26 and -30, consistent with a dominant negative effect. (Invest Ophthalmol Vis Sci. 2005;46:1957‐1965) DOI:10.1167/iovs.04-1364

In vivo and in vitro expression of connexins in the human corneal epithelium

Porokeratosis represents a spectrum of clinical disease. Multiple variants have been described including porokeratosis ptychotropica, a rare subtype. The clinical presentation of porokeratosis ptychotropica frequently resembles an inflammatory perianal disease. We report a patient with porokeratosis ptychotropica with coexistent disseminated superficial actinic porokeratosis. We review the current literature on porokeratosis ptychotropica including the clinical presentation, histopathology, cause, and pathogenesis of this rare variant of porokeratosis.

Porokeratosis ptychotropica: A clinically distinct variant of porokeratosis

Lichen planus confined to a radiation field: the "isoradiotopic" response.

We report on two young adults with KID syndrome and follicular hyperkeratosis, hidradenitis suppurativa of the groin, progressive development of proliferative pilar cysts and dissecting cellulitis of the scalp, who developed metastatic malignant pilar tumors. Based on our findings, we believe that cancer surveillance in patients with KID syndrome should include screening for pilar tumors and their early removal to avoid development of malignant proliferating pilar tumors with poor prognosis.

Daniel L. Shurman

Papers

Mutations in GALNT3 , encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis

In vivo and in vitro expression of connexins in the human corneal epithelium

Porokeratosis ptychotropica: A clinically distinct variant of porokeratosis

Lichen planus confined to a radiation field: the "isoradiotopic" response.

Malignant proliferating pilar tumors arising in KID syndrome: a report of two patients.