News & Views in 2002

Polyubiquitin chains are assembled onto proteins destined for degradation. The target protein is then unfolded by the proteasome and translocated through a channel leading from the unfolding site to an internal chamber of the enzyme for hydrolysis. A recent paper illuminates the long-elusive polyubiquitin chain recognition step that initiates this sequence of events at the proteasome.

The anaphase-promoting complex (APC) initiates exit from mitosis by ubiquitinating A- and B-type cyclins, the activating subunits of cyclin-dependent kinase 1 (Cdk1). Subsequently, the APC has to be inactivated to allow the re-accumulation of mitotic cyclins in the next cell cycle. A newly identified inhibitor of the APC, called Emi1 in vertebrates and Rca1 in Drosophila melanogaster, may have an important function in inactivating the APC during interphase.

Activation of tyrosine kinase receptors in epithelial cells results in the rapid disassembly of E-cadherin-mediated cell–cell adhesions. New research has identified Hakai, an E3-ubiquitin-ligase related to Cbl that binds E-cadherin in a tyrosine phosphorylation-dependent manner. By promoting the endocytosis and dynamic recycling or destruction of E-cadherin complexes, Hakai may control epithelial–mesenchymal transitions under physiological and pathological conditions.

Human herpesvirus 8 (HHV-8), an agent associated with Kaposi's sarcoma, binds to integrin α₃β₁ through its gB envelope glycoprotein, and thus gains entry into human fibroblasts. Based on an analogy with other microbial pathogens, integrin interaction with HHV-8 may induce signalling events that promote cell entry and perhaps facilitate disease progression.

Integrins are receptors for extracellular matrix proteins that engage in reciprocal crosstalk with growth factor receptors. Recent work identifies a unique mechanism for the regulation of growth factor receptor phosphorylation by integrins, indicating multiple ways of achieving cooperation between these major signalling systems.

Small GTPases of the Rab family are essential for the control of membrane transport between intracellular compartments. Recent work has shown that on melanosome membranes, Rab27a initiates the formation of a receptor complex that allows the recruitment of the actin-based motor myosin Va. This study provides a molecular basis for several pathologies that result in pigmentation defects in both mouse and humans.

Mutations in either of two polycystin genes can cause kidney failure, but controversy remains regarding the cellular localization and function of the protein products. Polycystin-2 may be a calcium release channel located within the endoplasmic reticulum (ER), and yet may be physically linked to polycystin-1 in the surface membrane.

The assembly of the DNA helicase at replication origins is crucial in initiating DNA synthesis. This process requires the conserved protein Cdt1. Here, a new study identifies a functional homologue of Cdt1 in Saccharomyces cerevisiae. The regulation of its activity reveals an alternative way to assemble prereplicative complexes (pre-RCs) and regulate origin function.

The positioning of a gene within the nucleus is thought to help regulate its transcriptional state. An example is yeast telomeres, which have a propensity to cluster at the nuclear periphery and suppress subtelomeric genes. With a membrane anchoring technique, new data indicate that there may be a second class of perinuclear silencing sites, which require pore-associated myosin-like proteins to establish repression.

The Arp2/3 complex has emerged as a key regulator of signal-dependent changes in the actin cytoskeleton. Recent biochemical and structural studies provide a wealth of information about how the assembly is regulated by WASP family members and actin filaments, and raise important new questions about this cellular machine.

The formin family of proteins have been implicated in regulation of cell polarity and cytoskeletal function in fungal and animal cells, but the manner in which they affect these processes has been mysterious. Two new studies report that formins in budding yeast are specifically required for the assembly of bundles of parallel actin filaments known as cables.

Early endosomes are the first sorting station from which endocytosed materials are targeted to various intracellular destinations. Recent work has identified the FYVE-domain protein rabenosyn-5 as a bifunctional effector of the GTPases rab5 and rab4, physically connecting entry and recycling sites on early endosomes.