Disease relevance of GLMN

• Immunophilins, Refsum disease, and lupus nephritis: the peroxisomal enzyme phytanoyl-COA alpha-hydroxylase is a new FKBP-associated protein [1].
• Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations ("glomangiomas") [2].
• Duodenal endocrine cells in 11 patients with familial amyloid associated polyneuropathy (FAP) were compared with those in 12 healthy volunteers by means of immunohistochemistry and morphometry [3].
• The primary objective of this study was to evaluate the clinical significance of stromal FAP in human colon cancers by immunohistochemisty [4].
• Xenotransplanted human colorectal tumors in mice were examined similarly for stromal FAP in tumors of different sizes [4].

High impact information on GLMN

• To specifically kill tumor-associated fibroblasts, we constructed an oral DNA vaccine targeting fibroblast activation protein (FAP), which is specifically overexpressed by fibroblasts in the tumor stroma [5].
• The FKBP-associated protein FAP48 is an antiproliferative molecule and a player in T cell activation that increases IL2 synthesis [6].
• FAP48 affects neither the calcineurin-dependent nuclear factor of activated T cells (NFAT)1 nor JNKp38-dependent pathways that mediate immunosuppression by FK506 [6].
• The present work describes the biochemical consequences of FAP48 overexpression, induced by the tetracycline analogue doxycycline, in an established cell line derived from Jurkat T cells [6].
• The abnormal phenotype of vascular smooth-muscle cells (VSMCs) in GVMs suggests that glomulin plays an important role in differentiation of these cells--and, thereby, in vascular morphogenesis--especially in cutaneous veins [2].

Biological context of GLMN

• We report that overexpression of FAP48 results in the inhibition of cellular proliferation as does the exposure of Jurkat T cells to FK506 [6].
• Recent studies have shown that mutations in the glomulin gene (GLMN) on chromosome 1p21-22 are responsible for familial GVMs [7].
• We also identified linkage disequilibrium that allowed a narrowing of this VMGLOM locus to 1.48 Mb [2].
• Here we show that VMs with glomus cells (known as "glomangiomas"), inherited as an autosomal dominant trait in five families, are not linked to 9p21 but, instead, link to a new locus, on 1p21-p22, called "VMGLOM" (LOD score 12.70 at recombination fraction.00) [8].
• We also demonstrated in vitro and in vivo, by Forster resonance energy transfer, that this C-terminal region is required for interaction with FAN (FKBP-associated NAC), a new member of the plant-specific family of NAC transcription factors [9].

Anatomical context of GLMN

• Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor [10].
• Here we show that epithelial cells, in which the HGF receptor is naturally expressed, contain FAP68 and not FAP48 proteins [10].
• We have investigated the adherence of a sputum isolate of MAC to the mucosa of organ cultures constructed with human tissue and the contribution of M. avium fibronectin attachment protein (FAP) to the process [11].
• Amyloid deposits were noted in seven of the 11 biopsy specimens from FAP patients, but otherwise the duodenum was histologically normal in both groups [3].

Associations of GLMN with chemical compounds

• Indeed, FAP68 does not interact with related tyrosine kinases of the Met and insulin receptor families [10].
• Mutation of proline 219 to alanine leads to a loss of interaction indicating that a cysteinyl prolyl site might be responsible for the binding of FAP48 to FKBPs [12].
• Familial amyloid protein (FAP), prealbumin type, can stand 2 hr of alkaline guanidine treatment without losing its ability to stain with Congo red [13].

Physical interactions of GLMN

• FAP68 interacts specifically with the inactive form of HGF receptor, such as a kinase-defective receptor or a dephosphorylated wild type receptor [10].

Regulatory relationships of GLMN

• Significantly, nonphosphorylated HGF receptor prevents FAP68 from stimulating p70S6K [10].

Other interactions of GLMN

• The formation of the complexes between FKBP59 or FKBP12 and FAP48 is prevented by FK506 and rapamycin in a dose-dependent manner [14].
• FAP68 binding to Met requires the last 30 amino acids of the C-terminal tail, which are unique to the HGF receptor [10].
• FK506 binding protein associated with the calcium release channel (ryanodine receptor) [15].
• In vivo, endogenous FAP68 can be coimmunoprecipitated with the HGF receptor in the absence of stimuli and not upon HGF stimulation [10].
• Mutation of FKBP associated protein 48 (FAP48) at proline 219 disrupts the interaction with FKBP12 and FKBP52 [12].

Analytical, diagnostic and therapeutic context of GLMN

• Stromal FAP was found to correlate inversely with tumor stage (semiquantitative, P = 0.01; intensity, P = 0.009) and with tumor size of the tumor xenograft model (correlation coefficient, -0.61; P = 0.047), suggesting that stromal FAP may have a greater role in the early development of tumors [4].
• FAP overexpression in human tumor cells has been shown to promote tumor growth in animal models, and clinical trials targeting FAP enzymatic activity have been initiated [4].
• SDS-PAGE analyses demonstrated that neither FAP nor APCE cleaves collagen I [16].
• This approach may play a role in inducing tolerance for solid organ transplantation and in utilizing the GVM effect to treat solid tumors that are not fully responsive to myeloablative cytotoxic regimens [17].
• Thus, efforts to separate GVM and GVHD are still required in order to improve the outcome of myeloma patients receiving allogeneic transplantation [18].

References