Phosphorylation of serine-893 in CARD11 suppresses the formation and activity of the CARD11-BCL10-MALT1 complex in T and B cells

CARD 11 acts as a gatekeeper for adaptive immune responses after T cell or B cell antigen receptor (TCR/BCR) ligation on lymphocytes. PKC theta/beta-catalyzed phosphorylation of CARD11 promotes the assembly of the CARD11-BCL10-MALT1 (CBM) complex and lymphocyte activation. Here, we demonstrated that PKC theta/beta-dependent CARD11 phosphorylation also suppressed CARD11 functions in T or B cells. Through mass spectrometry-based proteomics analysis, we identified multiple constitutive and inducible CARD11 phosphorylation sites in T cells. We demonstrated that a single TCR- or BCR-inducible phosphorylation on Ser 893 in the carboxyl terminus of CARD1 1 prevented the activation of the transcription factor NF-kappa B, the kinase JNK, and the protease MALT1. Moreover, CARD11 Ser(893) phosphorylation sensitized BCR-addicted lymphoma cells to toxicity induced by Bruton's tyrosine kinase (BTK) inhibitors. Phosphorylation of Ser 893 in CARD11 by PKCO controlled the strength of CARD11 scaffolding by impairing the formation of the CBM complex. Thus, PKCO simultaneously catalyzes both stimulatory and inhibitory CARD11 phosphorylation events, which shape the strength of CARD11 signaling in lymphocytes

MALT1 Phosphorylation Controls Activation of T Lymphocytes and Survival of ABC-DLBCL Tumor Cells

The CARMA1/CARD11-BCL10-MALT1 (CBM) complex bridges T and B cell antigen receptor (TCR/BCR) ligation to MALT1 protease activation and canonical nuclear factor kappa B (NF-kappa B) signaling. Using unbiased mass spectrometry, we discover multiple serine phosphorylation sites in the MALT1 C terminus after T cell activation. Phospho-specific antibodies reveal that CBM-associated MALT1 is transiently hyper-phosphorylated upon TCR/CD28 co-stimulation. We identify a dual role for CK1 alpha as a kinase that is essential for CBM signalosome assembly as well as MALT1 phosphorylation. Although MALT1 phosphorylation is largely dispensable for protease activity, it fosters canonical NF-kappa B signaling in Jurkat and murine CD4 T cells. Moreover, constitutive MALT1 phosphorylation promotes survival of activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) cells addicted to chronic BCR signaling. Thus, MALT1 phosphorylation triggers optimal NF-kappa B activation in lymphocytes and survival of lymphoma cells

Systems-level analysis reveals multiple modulators of epithelial-mesenchymal transition and identifies DNAJB4 and CD81 as novel metastasis inducers in breast cancer

Epithelial-mesenchymal transition (EMT) is driven by complex signaling events that induce dramatic biochemical and morphological changes whereby epithelial cells are converted into cancer cells. However, the underlying molecular mechanisms remain elusive. Here, we used mass spectrometry based quantitative proteomics approach to systematically analyze the post-translational biochemical changes that drive differentiation of human mammary epithelial (HMLE) cells into mesenchymal. We identified 314 proteins out of more than 6,000 unique proteins and 871 phosphopeptides out of more than 7,000 unique phosphopeptides as differentially regulated. We found that phosphoproteome is more unstable and prone to changes during EMT compared with the proteome and multiple alterations at proteome level are not thoroughly represented by transcriptional data highlighting the necessity of proteome level analysis. We discovered cell state specific signaling pathways, such as Hippo, sphingolipid signaling, and unfolded protein response (UPR) by modeling the networks of regulated proteins and potential kinase-substrate groups. We identified two novel factors for EMT whose expression increased on EMT induction: DnaJ heat shock protein family (Hsp40) member B4 (DNAJB4) and cluster of differentiation 81 (CD81). Suppression of DNAJB4 or CD81 in mesenchymal breast cancer cells resulted in decreased cell migration in vitro and led to reduced primary tumor growth, extravasation, and lung metastasis in vivo. Overall, we performed the global proteomic and phosphoproteomic analyses of EMT, identified and validated new mRNA and/ or protein level modulators of EMT. This work also provides a unique platform and resource for future studies focusing on metastasis and drug resistanceTurkiye Cumhuriyeti Kalkinma Bakanlig

Cassini Radio Science

Cassini radio science investigations will be conducted both during the cruise (gravitational wave and conjunction experiments) and the Saturnian tour of the mission (atmospheric and ionospheric occultations, ring occultations, determinations of masses and gravity fields). New technologies in the construction of the instrument, which consists of a portion on-board the spacecraft and another portion on the ground, including the use of the Ka-band signal in addition to that of the S- and X-bands, open opportunities for important discoveries in each of the above scientific areas, due to increased accuracy, resolution, sensitivity, and dynamic range.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43765/1/11214_2004_Article_1436.pd

Cutaneous involvement in sarcoidosis: Analysis of the features in 170 patients

In our study, we retrospectively evaluated the clinical features of patients diagnosed as sarcoidosis at our center within the Last 36 years and who had skin involvement. Cutaneous involvement was observed in 170 patients (32.9%, 136 females, 34 mates). The most frequent skin lesion was erythema nodosum (EN) (106 subjects, 20.5%). In addition, skin plaques and subcutaneous nodules were observed in 22 cases (4.3%), maculopapular eruptions in 19 cases (3.7%), scar lesions in 15 cases (2.9%), lupus pernio (LP) in 14 cases (2.7%) and psoriasiform plaques in five cases (0.9%). Among patients with LP (64.3%) and scar lesions (40%), pulmonary parenchymal involvement was more frequent than patients with other skin lesions. Parenchymal. involvement present in 10.4% of patients with EN was significantly less than in patients with LP and scar lesions (P values, respectively, <0.001, 0.002). When patients with skin involvement were compared to other sarcoidosis patients, it was seen that the frequency of females among those with skin involvement was significantly higher than the frequency among other sarcoidosis patients (P<0.001). Parenchymal involvement in sarcoidosis patients without skin involvement was less frequent than in patients with LP; however, more frequent than in patients with EN (both P values=0.002). As a conclusion, skin involvement was diagnosed in approximately one-third of our sarcoidosis patients with a generally female predominance. EN was the most frequent skin lesion encountered. Parenchymal involvement was more frequent in patients with LP and scar lesions and less frequent in patients with EN. (C) 2003 Elsevier Science Ltd. All rights reserved

Lofgren syndrome in Turkey

In the 36-year period between 1966 and 2002, 514 patients were diagnosed with sarcoidosis at Cerrahpala Medical Faculty, Gstanbul, Turkey, and of these 98 (19.1%) had Lofgren syndrome. The frequency of female patients with Lofgren was higher than the frequency among other sarcoidosis patients (female : male ratio 4.8 vs. 1.64; P < 0.001). Erythema nodosum was diagnosed in 72.4% of the subjects and arthritis or arthralgia was diagnosed in 51%. Erythema nodosum and arthritis or arthralgia were more frequent in Lofgren; however, pulmonary parenchymal involvement was more frequent in other sarcoidosis patients (all P-values < 0.001)

Bone marrow involvement in sarcoidosis: an analysis of 50 bone marrow samples

The incidence of bone marrow involvement in sarcoidosis patients and changes in their peripheral blood parameters have been investigated. Out of 92 patients diagnosed with sarcoidosis at our center between 1994 and 2002, 50 (54.3%) gave consent for a bone marrow biopsy and were included into our study. The clinical features, peripheral blood parameters and bone marrow biopsy findings of the patients were analysed. Of these 50 patients, 39 were females and 11 were males (median age 37 years, range 16-62). Anemia was detected in 11 (22%) cases, and both anemia and leucopenia in 3 (6%). In 10% (5 patients; 3 males, 2 females) of the patients, bone marrow biopsy revealed noncaseified granulomas. Sarcoidosis patients with bone marrow involvement had higher incidences of extrapulmonary involvement, leucopenia-lymphopenia and anemia than those without involvement (P values were, 0.05, 0.001 and 0.06, respectively). Of the 11 patients with anemia, 3 had involvement of the bone marrow by sarcoidosis and 7 had iron deficiency anemia. As a result, bone marrow involvement should be considered in sarcoidosis patients with anemia, leucopenia-lymphopenia, and also extrapulmonary involvement