Summary The aging suppressor αKlotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion/vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex consisting of the shed extracellular domain of αKlotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, αKlotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability. The endocrine character of FGF23 notwithstanding, dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signaling. The structure of αKlotho is incompatible with its purported glycosidase activity. Thus, shed αKlotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signaling.

No abstract

In China, family doctor services originated in 2009. After two years, the Chinese government proposed the establishment of a family doctor contract system suitable for China’s national conditions. Then, in 2016, a multi-department jointly issued an important document, which further clarified the development goals of family doctor contract services in the next five years. Zhejiang Province has been exploring responsible doctor contract services since 2012, which was promoted throughout the province in 2015. Objectives: The aim of this study was to investigate the residents’ awareness of Zhejiang Province, China, of family doctor contract services, the status of signing such a contract, and the demand for service items in the contracted service package. Further, we sought to explore the relevant influential factors in order to provide a reference and evidence-based recommendations for the further development of family doctor contract services. Design: We enrolled 3960 residents from nine counties in Zhejiang Province using a multistage stratified random sampling method. A survey using a self-designed questionnaire was used to collect the demographic data, residents’ awareness of family doctor contract services, the status of contracting, and demand for different items from October to December 2017. Data were analyzed by SPSS 21.0. Results: In total, 3871 residents returned valid questionnaires, with a response rate of 97.75%. The awareness rate of residents of family doctor contract services was 71.58% (2771/3871). Age, education level, and chronic medical history status were the influencing factors affecting residents’ awareness. The contracted rate was 50.43% (1952/3871). Age, education level, personal monthly income, chronic disease history, and awareness of family doctor contract services were the influencing factors. Residents who have a contract with family doctors have a higher demand for family doctor contract services, and different residents have different needs for the project because of their physical condition, education level, marital status, household registration, and personal monthly income level. The top three needs of the residents for contracted services were health consultation (84.64%), regular physical examination (81.71%), and increasing the proportion of medical insurance reimbursements (80.06%). Conclusions: The awareness rate of family doctor contract services and the contracting rate are unsatisfactory among residents of Zhejiang Province. It is suggested that the government should more heavily publicize family doctor contract services, expand the coverage, introduce personalized contract schemes to meet the needs of different groups, and promote the rapid development of family doctor contract services in Zhejiang Province.

The atypical cadherins, Fat (Ft) and Dachsous (Ds) control tissue growth via the Salvador-Warts-Hippo (SWH) pathway, and also regulate planar cell polarity (PCP), proximo-distal (PD) patterning and morphogenesis. Ft and Ds engage in reciprocal signalling as both proteins can serve as receptor and ligand for each other. The intracellular domains (ICD) of Ft and Ds regulate activity of the key SWH pathway transcriptional co-activator protein Yorkie (Yki). Signalling from the Ft ICD is well characterized and controls tissue growth by regulating abundance of the Ykirepressive kinase Warts (Wts). Here we describe two new regulators of the SWH pathway that function downstream of the Ds ICD: the WD40 domain protein Riquiqui (Riq) and the DYRK-family kinase Minibrain (Mnb). Ds physically interacts with Riq, which forms a complex with both Mnb and Wts. Riq and Mnb promote Ykidependent tissue growth by stimulating phosphorylation-dependent inhibition of Wts. Thus, we describe a new branch of the SWH pathway that promotes tissue growth downstream of Ds.

The Hippo pathway is a conserved signaling cascade that modulates tissue growth. Although its core elements are well defined, factors modulating Hippo transcriptional outputs remain elusive. Here we show that elements of the steroid-responsive ecdysone (Ec) pathway modulate Hippo transcriptional effects in imaginal disc cells. The Ec receptor coactivator Taiman (Tai) interacts with the Hippo transcriptional coactivator Yorkie (Yki) and promotes expression of canonical Yki-responsive genes. Tai enhances Yki-driven growth while Tai loss, or a form of Tai unable to bind Yki, suppresses Yki-driven tissue growth. This growth suppression is not correlated with impaired induction of canonical Hippo-responsive genes but with suppression of a distinct pro-growth program of Yki-induced/Tai-dependent genes, including the germline stem cell factors nanos and piwi. These data reveal Hippo/Ec pathway crosstalk in the form a Yki-Tai complex that collaboratively induces germline genes as part of a transcriptional program that is normally repressed in developing somatic epithelia.

Defective expression of LATS2, a negative regulator of YAP oncoprotein, has been reported in cancer of prostate, breast, liver, brain, and blood origins. However, no transcriptional regulators for the LATS2 gene have been identified. Here we report that spontaneous mutation of the transcription factor FOXP3 reduces expression of the LATS2 gene in mammary epithelial cells. shRNA-mediated silencing of FOXP3 in normal or malignant mammary epithelial cells of mouse and human origin repressed LATS2 expression and increased YAP protein levels. LATS2 induction required binding of FOXP3 to a specific sequence in the LATS2 promoter, and this interaction contributed to FOXP3-mediated growth inhibition of tumor cells. In support of these results, reduced expression and somatic mutations of FOXP3 correlated strongly with defective LATS2 expression in microdissected prostate cancer tissues. Thus, defective expression of LATS2 is attributable to FOXP3 defects and may be a major independent determinant of YAP protein elevation in cancer. Our findings identify a novel mechanism of LATS2 downregulation in cancer and reveal an important tumor suppressor relay between the FOXP3 and HIPPO pathways which are widely implicated in human cancer. Cancer Res; 71(6); 2162-71. Ó2011 AACR.

No abstract

The transcriptional repressor Capicua (Cic) controls tissue patterning and restricts organ growth, and has been recently implicated in several cancers. Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. We found that the kinase Minibrain (Mnb, ortholog of mammalian DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein. Mnb and Wap inhibit Cic function by limiting its transcriptional repressor activity. Down-regulation of Cic by Mnb/Wap is necessary for promoting the growth of multiple organs, including the wings, eyes, and the brain, and for proper tissue patterning in the wing. We have thus uncovered a previously unknown mechanism of down-regulation of Cic activity by Mnb and Wap, which operates independently from the ERK-mediated control of Cic. Therefore, Cic functions as an integrator of upstream signals that are essential for tissue patterning and organ growth. Finally, because DYRK1A and CIC exhibit, respectively, prooncogenic vs. tumor suppressor activities in human oligodendroglioma, our results raise the possibility that DYRK1A may also down-regulate CIC in human cells.