Disease relevance of AMFR

• The autocrine motility factor (AMF) is known as a cytokine regulating tumor cells motility via AMF receptor (AMFR) and promotes their metastasis [1].
• We assessed the possible correlation between AMFR, clinicopathologic features, and survival in stage I non-small cell lung cancer (NSCLC) [2].
• The AMFR expression was significantly associated with histologic type of tumor, mainly in adenocarcinoma [2].
• The connection between AMFR expression and the invasive/metastatic potential of melanoma was further supported by our observation that SSM melanoma in the vertical growth phase expressed this motility receptor more strongly than tumors in the radial growth phase [3].
• The motility stimulation of the fibrosarcoma cells with AMF is associated with the phosphorylation of the AMF receptor, a 78-kDa cell surface glycoprotein (gp78), suggesting protein kinase participation in migratory signal transduction [4].

Psychiatry related information on AMFR

• The reduced AMFR in listeners with dyslexia may reflect impaired ability of the auditory system to follow rapid changes in stimulus energy, a cue believed to be important in the perception of speech [5].
• Second, a parallel increase was found in hippocampal NLK and gp78 proteins after maze learning [6].

High impact information on AMFR

• Here, we show that gp78, a membrane bound E3, binds to Insig-1 and is required for sterol-regulated ubiquitination of reductase [7].
• In addition, gp78 couples regulated ubiquitination to degradation of reductase by binding to VCP, an ATPase that plays a key role in recognition and degradation of ERAD substrates [7].
• The AMF-R tubule is therefore not a biosynthetic subcompartment of the endoplasmic reticulum [8].
• Autocrine motility factor receptor is a marker for a distinct membranous tubular organelle [8].
• The tubular morphology of the AMF-R tubule is modulated by both the actin and microtubule cytoskeletons [8].

Chemical compound and disease context of AMFR

• Similar to previous studies on murine melanoma, activation of the AMF receptor upregulated beta3 while it downregulated beta1 integrins at the cell surface, inducing an integrin phenotype characteristic for invasive/metastatic melanoma [3].
• Activation of the cell surface receptor for AMF (gp78) was shown to stimulate production of a 12-lipoxygenase metabolite of arachidonic acid, 12-(S)-hydroxyeicosatetraenoic acid [12-(S)-HETE], in highly metastatic murine melanoma cells [9].
• Sodium dodecylsulfate polyacrylamide gel electrophoresis of 125I-labeled HepG2 membrane protein precipitated with IgG from patients with alcoholic liver diseases revealed an immunoreactive band at a molecular weight of 78,000 daltons (gp78) [10].

Biological context of AMFR

• BACKGROUND: Expression of autocrine motility factor receptor (AMFR) associates with increased cell migration and poor survival in certain types of human cancers [2].
• Chloramphenicol Acetyl Transferase (CAT) reporter gene assays have identified this region as the promoter of the hAMFR gene [11].
• We have isolated from a human placenta cosmid library a 0.7 kb genomic clone that contains the 5' terminal portion of the autocrine motility factor receptor (hAMFR) coding region [11].
• These studies revealed three types of AMF receptor phenotype: weak, heterogenous and strong expression profile [3].
• Autocrine motility factor-receptor gene expression in lung cancer [12].

Anatomical context of AMFR

• The gene product of the gp78/AMFR ubiquitin E3 ligase cDNA is selectively recognized by the 3F3A antibody within a subdomain of the endoplasmic reticulum [13].
• The gp78/AMF receptor protein expression in human melanoma cell lines correlated to their in vivo spontaneous metastatic potential [3].
• The AMF-R gene expression was significantly associated with lymph node metastasis, and stage [12].
• Mutant AMFR lacking the N-sugar chain was expressed on the cell membrane but did not respond to AMF-stimulation, and N-glycosidase-treated AMFR did not compete with receptor binding of AMF [14].
• Normal gastric mucosa (control) reacted strongly for ECD and weakly for AMFR [15].

Associations of AMFR with chemical compounds

• These signals are triggered by binding between AMF and its receptor (AMFR), a glycoprotein on the cell surface [14].
• Studies with AMFR (autocrine motility factor receptor) have defined an SER domain whose integrity and mitochondrial association can be modulated by ilimaquinone as well as by free cytosolic calcium levels in the normal physiological range [16].
• In addition to being expressed on the cell surface, its receptor, AMF-R, is found within a Triton X-100 extractable intracellular tubular compartment [8].
• By immunofluorescence microscopy, AMF-R tubules are clearly distinguished from the calnexin labeled rough endoplasmic reticulum and AMF-R tubule expression is stable to extended cycloheximide treatment [8].
• This gp78-regulated increase is mediated by up-regulation of surface alphaIIbbeta3++ and alpha5beta1 integrin receptors [17].

Physical interactions of AMFR

• In contrast, gp78 lacking an intact RING finger or its multiple membrane-spanning domains stabilizes CD3-delta. gp78 has thus been found to be an example of a mammalian cellular E3 intrinsic to the ER, suggesting a potential link between ubiquitylation, ERAD, and metastasis [18].
• Sterol-regulated Degradation of Insig-1 Mediated by the Membrane-bound Ubiquitin Ligase gp78 [19].

Regulatory relationships of AMFR

• However, both p97/VCP and Ufd1 appear to be required for CD3delta degradation in cells expressing physiological levels of gp78 [20].

Other interactions of AMFR

• The AMFR expression appears to be associated with VEGF expression [2].
• Importantly, gp78 can also mediate degradation of CD3-delta, a well-characterized ERAD substrate [18].
• Overexpression of the tumor autocrine motility factor receptor Gp78, a ubiquitin protein ligase, results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in HepG2 cells [21].
• This action of gp78 was specific: overexpression of the protein did not affect secretion of either albumin or apolipoprotein AI [21].
• Inhibition of p97/VCP, but not Ufd1, stabilized CD3delta in cells that overexpress gp78 [20].

Analytical, diagnostic and therapeutic context of AMFR

• The FLAG-taggedAMFR immunoprecipitated with an anti-FLAG antibody was recognized by the 3F3A mAb in Western blot analysis and cells transfected with AMFR exhibit increased labeling with the 3F3A mAb [13].
• METHODS: Using reverse transcription-polymerase chain reaction (RT-PCR) analyses and phagokinetic assay, we studied the correlation between the level of AMF-R gene expression and cell motility [12].
• The expression of c-Met, AMFR, and Ets-1 protein was analyzed by immunohistochemistry in 99 patients with tongue SCC [22].
• Moreover, patients with increased expression of both c-Met and AMFR had significantly worse disease-free survival [22].
• CONCLUSIONS: These results suggest that the expression patterns of c-met, AMFR, and uPAR may be closely associated with the progression and invasion of gastric carcinoma as well as the prognoses of the patients [23].

References