Timeline

Protein methylation was discovered over 50 years ago, but only with the advent of genomic and proteomic technologies could its mechanisms and cellular functions be studied in detail. Shi and Murn discuss the seminal discoveries in protein methylation research and highlight future directions for this field.

Several years after the characterization of the role of receptor-interacting serine/threonine protein kinase 1 (RIPK1) in cell survival, inflammation and disease, RIPK1 was implicated in the regulation of a newly identified type of cell death known as necroptosis. This Timeline article describes the discoveries that shed light on the roles of RIPK1, RIPK3, mixed-lineage kinase domain-like protein (MLKL) and other regulators of necroptosis in controlling cell fate.

This year marks the tenth anniversary of the generation of induced pluripotent stem cells (iPSCs) by transcription factor-mediated somatic cell reprogramming. Takahashi and Yamanaka portray the path towards this ground-breaking discovery and discuss how, since then, research has focused on understanding the mechanisms underlying iPSC generation and on translating such advances to the clinic.

The discovery of modular protein- and lipid-binding domains was a crucial turning point in our understanding of the logic and evolution of cell signalling mechanisms. The late, great Tony Pawson was instrumental in their discovery.

The year 2014 marks the 50th anniversary of the discovery of protein acetylation. In this Timeline article, Verdin and Ott discuss the identification of this modification, of its regulatory enzymes and of the roles of acetylation in transcription and other cellular processes, and provide an outlook on the future of the field.

The form of vertebrates is shaped by the sensing and relaying of mechanical forces that are applied between cells and their microenvironment. Mechanobiology has emerged as a field of research dedicated to studying these forces and their communication through signalling processes, which are collectively known as mechanotransduction.

The concept of allosteric interactions between topographically distinct sites, and the subsequent Monod-Wyman-Changeux model proposed in 1965 for the conformational change mediating them, arose around 50 years ago. Many classic regulatory proteins follow this model, which has been expanded and challenged over the years.

Although the physiological importance of adhesion was appreciated early in the twentieth century, understanding its molecular basis was challenging. The development of complementary biochemical and immunological approaches facilitated the discovery of the cadherins, integrins and other major adhesion families and led to the molecular era of adhesion research and the formation of a new research community.

Phosphoinositide 3-kinase (PI3K) signalling is central in the regulation of cellular function. Here, Vanhaesebroecket al.review the key discoveries that led the identification of the PI3K genes and function to the design of clinical trials with PI3K inhibitors, over a period of less than three decades.

This year marks the thirtieth anniversary since embryonic stem (ES) cells were first isolated from mouse blastocysts. In this Timeline, one of the scientists to isolate mouse ES cells in 1981 gives a personal account of the ideas that led to, and followed, this milestone.

This timeline article pays tribute to the late James Fred 'Paulo' Dice, whose vision of selective protein degradation in lysosomes led to the discovery of chaperone-mediated autophagy.

In 1971, Günter Blobel and David Sabatini formulated the signal hypothesis, which proposed that proteins contain signal sequences that target them for secretion. Over the past 40 years this concept has expanded, and topogenic signals are now known to target proteins to many parts of the cell.

The determination of the first three-dimensional structure of a protein 50 years ago initiated the field of protein folding research. Technological and experimental advances, which were sometimes met with initial scepticism, have led to our present understanding of protein folding.

The idea that processes can be self-organized and self-reproducing is more than 100 years old. But self-organization principles that were first developed in chemistry and physics are only now beginning to be applied to cellular and subcellular morphogenesis.

Ten years ago, few people had heard of the term autophagy (literally 'self-eating'). But less than a decade later, research in the field has exploded, and recent studies have uncovered an integral role for autophagy in various human diseases.

SOS mutagenesis is the 'mutation-prone' cellular replication mechanism that is responsible for UV-induced mutations. More than 50 years of SOS mutagenesis research has exposed the underlying mechanisms of DNA-damage-induced mutagenesis that combine the overlapping functions of replication, repair and recombination.

The discovery of insulin in 1921 was one of the great medical advances of the twentieth century. Since then, key discoveries have led to a molecular understanding of the insulin-signalling pathway and revealed targets for the treatment of type-2 diabetes.

Self-regulation is one of the most intriguing properties of early embryos. In 1924, Spemann and Mangold carried out the most famous experiment in experimental embryology, which led to the identification of the first self-organizing centre — the Spemann's organizer.