ectodomains of the ldl receptor-related proteins lrp1b and lrp4 have anchorage independent functions in vivo低密度脂蛋白受体相关蛋白的ectodomains lrp1b和lrp4锚固体内独立函数.pdfVIP

Ectodomains of the LDL Receptor-Related Proteins LRP1b and LRP4 Have Anchorage Independent Functions In Vivo 1. 2. 3 3 1 Martin F. Dietrich , Louise van der Weyden , Haydn M. Prosser , Allan Bradley , Joachim Herz *, David J. Adams2* 1 Department of Molecular Genetics, UT Southwestern, Dallas, Texas, United States of America, 2 Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambs, United Kingdom, 3 Mouse Genomics, Wellcome Trust Sanger Institute, Hinxton, Cambs, United Kingdom Abstract Background: The low-density lipoprotein (LDL) receptor gene family is a highly conserved group of membrane receptors with diverse functions in developmental processes, lipoprotein trafficking, and cell signaling. The low-density lipoprotein (LDL) receptor-related protein 1b (LRP1B) was reported to be deleted in several types of human malignancies, including non-small cell lung cancer. Our group has previously reported that a distal extracellular truncation of murine Lrp1b that is predicted to secrete the entire intact extracellular domain (ECD) is fully viable with no apparent phenotype. Methods and Principal Findings: Here, we have used a gene targeting approach to create two mouse lines carrying internally rearranged exons of Lrp1b that are predicted to truncate the protein closer to the N-terminus and to prevent normal trafficking through the secretary pathway. Both mutations result in early embryonic lethality, but, as expected from the restricted expression pattern of LRP1b in vivo, loss of Lrp1b does not cause cellular lethality as homozygous Lrp1b- deficient blastocysts can be propagated normally in culture. This is similar to findings for another