Reviews & Analysis

Monoubiquitination of the Fanconi anaemia protein FANCD2 is essential for its activity in DNA repair and tumour suppression. The recent identification of a specific de-ubiquitinating (DUB) enzyme for FANCD2 raises intriguing questions about how and why this tumour suppressor becomes deactivated.

Many biological processes require the movement of cells in response to guidance cues. Small GTPases and phosphoinositides are key mediators of the underlying cytoskeletal rearrangements, and a new study establishes that the localization and activation of the phosphoinositide phosphatase PTEN at the rear of chemotaxing neutrophils is mediated by the small GTPase RhoA.

How cells establish and maintain polarity during directed cell migration remains poorly understood. Nishiya et al. now describe an integrin signalling complex that includes paxillin and GIT1, which limits activation of Rac to the leading edge of a migrating cell.

Epidermal growth factor and nerve growth factor (NGF) lead to significantly different temporal patterns of extracellular-signal-regulated kinase activation, and differential regulation of Ras and Rap1 have been implicated in mediating this temporal specificity. Now Sasagawa et al. derive a computational model that incorporates the known signalling interactions and identifies key points of regulation that control these processes.

In this issue, two groups have examined the role of the Par proteins in the regulation of small G proteins, in two different models of cell polarity — mammalian epithelia and neuronal axon specification. They concurrently report the intriguing finding that the Par-3/Par-6/aPKC complex can regulate the activation of Rac by interaction with the guanine nucleotide exchanger, Tiam1/STEF. Furthermore, they also demonstrate a hitherto under-appreciated role for the Par-3/Par-6/aPKC complex in the regulation of the actin cytoskeleton.

Targeting substrates to the proteasome is generally thought to depend on long polyubiquitin chains that form on the substrate. Recent work has led to the provocative proposal that some substrates may be targeted to the proteasome through smaller chains that contain only four to six ubiquitin molecules.

Nuclear accumulation of the c-Abl tyrosine kinase is associated with a pro-apoptotic response after DNA damage, but the mechanism regulating c-Abl nuclear localization is unclear. DNA damage and other stress signals are now shown to induce phosphorylation of 14-3-3 proteins by the c-Jun amino-terminal kinase, disrupting a c-Abl/14-3-3 cytoplasmic complex, and liberating c-Abl for translocation to the nucleus.

Cancer cells have a raised cellular metabolism, including increased protein biosynthesis. Three new studies now show that the oncoprotein Myc, known to drive cell division, also enhances ribosomal RNA synthesis by RNA polymerase I in addition to controlling RNA polymerase II- and III-regulated gene transcription. This suggests that Myc promotes the generation of crucial components of a functional ribosome.

Actin polymerization is intimately associated with endocytosis in yeast and mammalian cells. Mechanisms of actin filament assembly in endocytosis are becoming better understood but less is known about how assembly is terminated. In yeast, phosphorylation of Arp2/3 complex activators provides one mechanism for downregulating endocytic actin assembly.

The mammalian Forkhead Box M1 (FoxM1) protein, known for its function as a transcriptional regulator of G1/S progression, is also crucial for the G2/M transition. Some of its target genes are cyclin B, Cdc25B phosphatase, Aurora B kinase and Polo-like kinase. Furthermore, identification of the nuclear protein CENP-F as a transcriptional target of FoxM1 reveals how it can also regulate the spindle assembly checkpoint, thereby ensuring proper chromosome stability and segregation during mitosis.

Bcl-2 has previously been characterized as an anti-apoptotic protein. However, it has now been linked to DNA mismatch repair (MMR). By retaining E2F-1 in a transcriptionally inactive state, through the induction of hypophosphorylated retinoblastoma protein, Bcl-2 hinders the expression of a key component of mismatch repair, MSH2. This study could therefore help to explain the mutagenicity that is associated with Bcl-2.

How cells maintain the balance between membrane fission and fusion is not known. Recent results show that Vps1p, a yeast dynamin-like protein, is involved in both processes at the vacuole, indicating that these two antagonistic reactions might be connected after all.

Mechanosensitive channels are essential for effective cellular function, but elucidation of their molecular identity and mechanisms of activation has proven difficult. Two recent studies now implicate members of the transient receptor potential (TRP) family as components of the mechanosensitive channels in vertebrate hair cells (TRPA1) and stretch-activated channels (TRPC1) in several different vertebrate cell types.

Nuclear pore complexes intuitively seem functionally analogous to transmembrane channels. Recent bioinformatic analysis, however, suggests a quite different evolutionary relationship: one between nuclear pore complexes and vesicle coat components. This has led to the provocative hypothesis that these distinct structures share a common role in bending membranes.

The activation and targeted localization of ubiquitin E2 conjugating enzymes could provide a point for regulating ubiquitin-dependent cell functions. Supporting this view, the ubiquitin charging and activation of a class of E2 enzymes has been directly linked to their nuclear import.