The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune system

The Cbl family of proteins are evolutionarily conserved negative regulators of activated tyrosine kinase-coupled receptors. Antigen receptors are prominent targets of negative regulation by the Cbl family members, Cbl and Cbl-b, which proteins function as ubiquitin ligases. Cbl and Cbl-b contain substrate recognition domains that interact specifically with activated protein tyrosine kinases of the Src and Syk/ZAP-70 families. Cbl-mediated ubiquitination of these kinases leads to their degradation, resulting in attenuation of receptor signals. Cbl may also control activation-induced monoubiquitination of antigen receptors, thus facilitating their delivery to lysosomes for subsequent degradation. Finally, the interactions of Cbl proteins with downstream targets of tyrosine kinases, such as PI-3-kinase and Vav, could provide an additional mechanism to attenuate receptor signaling. By targeting multiple components of antigen receptor signaling for degradation, the Cbl protein family provides a critical mechanism to ensure an appropriate immune response. The hyperresponsiveness of Cbl(-/-) and Cbl-b(-/-) lymphocytes and the autoimmune phenotype of Cbl-b(-/-) mice lend strong support for this proposal. The ability to control early receptor signals through regulated protein degradation provides a novel paradigm of immunoregulation.     

Biochemical and biophysical analysis of heptad repeat regions from the fusion protein of Menangle virus,a newly emergent paramyxovirus

E. coli in vitro expression system. The GST-removed purified 2-Helix protein could form a stable trimer in vitro judging by gel-filtration and chemical cross-linking. CD spectra showed that the 2-Helix protein had a high percentage of α-helix and was very thermo-stable. Crystals of the 2-Helix protein preparations have been obtained in many conditions with hanging-drop diffusion method. These results indicated that Menangle virus has the common features of the fusion protein for other paramyxoviruses and should adopt a similar fusion mechanism to other members. As the HR regions of Menangle virus F protein could form stable six-helix bundle coiled coil structure, they should be used as drug target for the design of fusion inhibitors, as successfully used for other parmyxoviruses. This is especially relevant to such a newly emergent virus with zoonotic potentials. Received January 23, 2003; accepted February 28, 2003 Published online April 28, 2003     

Segmental jejunal lipomatosis--a rare cause of intestinal obstruction

A rare case of a segmental small intestinal (jejunal) lipomatosis is described. A 33-year-old male was admitted with a clinical diagnosis of an acute intestinal obstruction. A plain erect abdominal x-ray showed multiple air-fluid levels. On an exploratory laparotomy, a jejunojejunal intussusception was found secondary to a segmental submucosal lipomatosis. This was treated by a segmental resection and anastomosis, which resulted in a complete cure. Here we present this case with a review of the relevant literature.     

Dystrophin gene deletions in South Indian Duchenne muscular dystrophy patients

66 unrelated patients from Southern India with Duchenne Muscular Dystrophy (DMD) were studied for intragenic deletion in 18 exons and Pm region of the DMD gene using multiplex PCR. Of these 41 (62.1%) showed intragenic deletions. 78% of the deletions were located at the distal hotspot region (44-55 exons) and 22% of the deletions were located at the proximal region (exon 2-19). Exon 50 is most frequently deleted. Deletions in isolated cases were significantly more compared to familial cases. The lower incidence reported from South India compared to North India, is suggestive of variations in the Southern and Northern population.     

Alterations in hepatic kinase activity following whole body gamma-irradiation of mice

The chronological activation of the signaling molecules following whole body gamma-irradiation was investigated in mouse liver. The activity of two kinases, tyrosine kinase and protein kinase C (PKC), was found to respond differently to gamma-irradiation. Tyrosine kinase was found to respond to much lower doses of irradiation (10 cGy), whereas PKC was found to be activated at comparatively higher doses (3 Gy). Tyrosine kinase showed a sharp activation at 30 min and then a decline to normal values at 1 h. Activation of PKC was apparent at as early as 15 min of irradiation and showed a maximal increase at 30 min. This was followed by a decline to normal values at 1 h. The response of the whole organ was found to be different from that of reported effects on a single cell. These results suggest that the data obtained from the single-cell studies would have limited application in the experiments involving the whole animal. Interruption of these signals at various steps is currently being used to manipulate tumor response to radiotherapy. In such cases, the difference in response of a single cell and a whole animal must be considered.