SHARPIN is a ubiquitin-binding and ubiquitin-like domain-containing protein which, when mutated in mice, results in immune system disorders and multiorgan inflammation1,2. Here we report that SHARPIN functions as a novel component of the Linear Ubiquitin Chain Assembly Complex (LUBAC) and that the absence of SHARPIN causes disregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis in SHARPIN deficient mice. Upon binding to the LUBAC subunit HOIP, SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Co-expression of SHARPIN and HOIP promotes linear ubiquitylation of NEMO, an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, while SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages, and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L, another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon TNFα stimulation via FADD- and Caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.

RTKs (receptor tyrosine kinases) play important roles in cellular proliferation and differentiation. In addition, RTKs reveal oncogenic potential when their kinase activities are constitutively enhanced by point mutation, amplification or rearrangement of the corresponding genes. The ALK (anaplastic lymphoma kinase) RTK was originally identified as a member of the insulin receptor subfamily of RTKs that acquires transforming capability when truncated and fused to NPM (nucleophosmin) in the t(2;5) chromosomal rearrangement associated with ALCL (anaplastic large cell lymphoma). To date, many chromosomal rearrangements leading to enhanced ALK activity have been described and are implicated in a number of cancer types. Recent reports of the EML4 (echinoderm microtubule-associated protein like 4)–ALK oncoprotein in NSCLC (non-small cell lung cancer), together with the identification of activating point mutations in neuroblastoma, have highlighted ALK as a significant player and target for drug development in cancer. In the present review we address the role of ALK in development and disease and discuss implications for the future.

In the past decade, the diversity of signals generated by the ubiquitin system has emerged as a dominant regulator of biological processes and propagation of information in the eukaryotic cell. A wealth of information has been gained about the crucial role of spatial and temporal regulation of ubiquitin species of different lengths and linkages in the nuclear factor-κB (NF-κB) pathway, endocytic trafficking, protein degradation and DNA repair. This spatiotemporal regulation is achieved through sophisticated mechanisms of compartmentalization and sequential series of ubiquitylation events and signal decoding, which control diverse biological processes not only in the cell but also during the development of tissues and entire organisms.Ten years ago, we were only starting to suspect the leading part that the ubiquitin network was about to take in our understanding of cellular signalling. At that time, ubiquitylation was beginning to be acknowledged as more than simply a signal for protein degradation, and instead as a main regulator of biological events 1 . RING domains had been recognized as mediators of ubiquitin ligase activity, and differently linked ubiquitin chains were suspected to regulate distinct processes, as suggested by reports linking Lys63 ubiquitin chains to proinflammatory signalling pathways and DNA repair responses. Since then, the ubiquitin system has been found to be highly versatile, in terms of both the range of ubiquitin signals and the range of cellular responses that ubiquitin conjugation can trigger (BOX 1).Ubiquitylation is achieved by the concerted action of activating (E1), conjugating (E2) and ligating (E3) enzymes, some of which possess elongating activities that support the generation of polyubiquitin chains [2][3][4][5][6] . Proteins can be modified through the conjugation of monoubiquitin or polyubiquitin chains of variable length on any of the seven Lys residues (Lys6, Lys11, Lys27, Lys29, Lys33, Lys48 or Lys63) or the amino-terminal Met (Met1) of the ubiquitin monomer. Ubiquitin chains can thus be connected by at least eight different homotypic linkages, as well as by a range of atypical chains (heterologous, forked or mixed) 5,7,8 . Occasionally, efficient protein polyubiquitylation requires additional conjugation factors, so-called E4 enzymes, that support the elongation of ubiquitin chains 9 (reviewed in REF. 10). The myriad of ubiquitin signal species is recognized and decoded by specialized ubiquitin-binding domains (UBDs), which form transient, non-covalent Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts interactions with either ubiquitin moieties or the linkage region in ubiquitin chains 11 . Strict control of ubiquitylation is accomplished by deubiquitylating enzymes (DUBs), a divergent family of isopeptidases that reverse ubiquitylation by removing conjugated ubiquitin tags 12,13 . Several recent reviews have elaborated on the principle mechanisms by which ubiquitylation is implicated in regulating different aspects of cellular phys...

The Drosophila melanogaster gene Anaplastic lymphoma kinase (Alk) is homologous to mammalian Alk, a member of the Alk/Ltk family of receptor tyrosine kinases (RTKs). We have previously shown that the Drosophila Alk RTK is crucial for visceral mesoderm development during early embryogenesis. Notably, observed Alk visceral mesoderm defects are highly reminiscent of the phenotype reported for the secreted molecule Jelly belly (Jeb). Here we show that Drosophila Alk is the receptor for Jeb in the developing visceral mesoderm, and that Jeb binding stimulates an Alk-driven, extracellular signal-regulated kinase-mediated signalling pathway, which results in the expression of the downstream gene duf (also known as kirre)--needed for muscle fusion. This new signal transduction pathway drives specification of the muscle founder cells, and the regulation of Duf expression by the Drosophila Alk RTK explains the visceral-mesoderm-specific muscle fusion defects observed in both Alk and jeb mutant animals.

Background: The mammalian receptor protein tyrosine kinase (RTK), Anaplastic Lymphoma Kinase (ALK), was first described as the product of the t(2;5) chromosomal translocation found in non-Hodgkin's lymphoma. While the mechanism of ALK activation in non-Hodgkin's lymphoma has been examined, to date, no in vivo role for this orphan insulin receptor family RTK has been described.

The Drosophila melanogaster gene Anaplastic lymphoma kinase (Alk) is homologous to mammalian Alk, which encodes a member of the Alk/Ltk family of receptor tyrosine kinases (RTKs). In humans, the t(2;5) translocation, which involves the ALK locus, produces an active form of ALK, which is the causative agent in non-Hodgkin's lymphoma. The physiological function of the Alk RTK, however, is unknown. In this paper, we describe loss-offunction mutants in the Drosophila Alk gene that cause a complete failure of the development of the gut. We propose that the main function of Drosophila Alk during early embryogenesis is in visceral mesoderm development.

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