Yan Shi1,2, Hefei Ruan1,3, Yanni Xu1 and Chunlin Zou1 1Department of Basic Medical Sciences, Tsinghua-Peking University Joint Center for Life Sciences, School of Medicine; Institute for Immunology, Tsinghua University, Beijing 100084, China 2Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, Alberta T2N 4Z6, Canada 3Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China Correspondence: yanshiemailmail.tsinghua.edu.cn

Transmembrane signaling is essential for complex life forms. Communication across a bilayer lipid barrier is elaborately organized to convey precision and to fine-tune strength. Looking back, the steps that it has taken to enable this seemingly mundane errand are breathtaking, and with our survivorship bias, Darwinian. While this review is to discuss eukaryotic membranes in biological functions for coherence and theoretical footing, we are obliged to follow the evolution of the biological membrane through time. Such a visit is necessary for our hypothesis that constraints posited on cellular functions are mainly via the biomembrane, and relaxation thereof in favor of a coordinating membrane environment is the molecular basis for the development of highly specialized cellular activities, among them transmembrane signaling. We discuss the obligatory paths that have led to eukaryotic membrane formation, its intrinsic ability to signal, and how it set up the platform for later integration of protein-based receptor activation.