How human FGFR1 localizes to the PM is unknown. Currently, it is assumed that newly synthesized FGFR1 is continuously delivered to the PM. However, evidence indicates that FGFR1 is mostly sequestered Show more
How human FGFR1 localizes to the PM is unknown. Currently, it is assumed that newly synthesized FGFR1 is continuously delivered to the PM. However, evidence indicates that FGFR1 is mostly sequestered in intracellular post-Golgi vesicles (PGVs) under normal conditions. In this report, live-cell imaging and total internal reflection fluorescence microscopy (TIRFM) were employed to study the dynamics of these FGFR1-positive vesicles. We designed recombinant proteins to target different transport components to and from the FGFR1 vesicles. Mouse embryoid bodies (mEBs) were used as a 3D model system to confirm major findings. Briefly, we found that Rab2a, Rab6a, Rab8a, RalA and caveolins are integral components of FGFR1-positive vesicles, representing a novel compartment. While intracellular sequestration prevented FGFR1 activation, serum starvation and hypoxia stimulated PM localization of FGFR1. Under these conditions, FGFR1 C-terminus acts as a scaffold to assemble proteins to (i) inactivate Rab2a and release sequestration, and (ii) assemble Rab6a for localized activation of Rab8a and RalA-exocyst to deliver the receptor to the PM. This novel pathway is named Regulated Anterograde RTK Transport (RART). This is the first instance of RTK regulated through control of PM delivery. Show less
Genome wide association studies (GWAS), mostly in Europeans have identified several common variants as associated with key lipid traits. Replication of these genetic effects in South Asian populations Show more
Genome wide association studies (GWAS), mostly in Europeans have identified several common variants as associated with key lipid traits. Replication of these genetic effects in South Asian populations is important since it would suggest wider relevance for these findings. Given the rising prevalence of metabolic disorders and heart disease in the Indian sub-continent, these studies could be of future clinical relevance. We studied seven common variants associated with a variety of lipid traits in previous GWASs. The study sample comprised of 3178 sib-pairs recruited as participants for the Indian Migration Study (IMS). Associations with various lipid parameters and quantitative traits were analyzed using the Fulker genetic association model. We replicated five of the 7 main effect associations with p-values ranging from 0.03 to 1.97x10(-7). We identified particularly strong association signals at rs662799 in APOA5 (beta=0.18 s.d, p=1.97 x 10(-7)), rs10503669 in LPL (beta =-0.18 s.d, p=1.0 x 10(-4)) and rs780094 in GCKR (beta=0.11 s.d, p=0.001) loci in relation to triglycerides. In addition, the GCKR variant was also associated with total cholesterol (beta=0.11 s.d, p=3.9x10(-4)). We also replicated the association of rs562338 in APOB (p=0.03) and rs4775041 in LIPC (p=0.007) with LDL-cholesterol and HDL-cholesterol respectively. We report associations of five loci with various lipid traits with the effect size consistent with the same reported in Europeans. These results indicate an overlap of genetic effects pertaining to lipid traits across the European and Indian populations. Show less