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The SH2-containing adapter protein GRB10 interacts with BCR-ABL

Bai RY; Jahn T; Schrem S; Munzert G; Weidner KM; Wang JY; Duyster J
Bcr-Abl is an oncogenic tyrosine kinase expressed in tumor cells of CML and a subset of ALL which in its unregulated and activated state is thought to cause cell transformation and leukemia. Bcr-Abl contains several autophosphorylation sites which serve as potential docking sites for SH2-containing signaling molecules. Mutational analysis has indicated that these autophosphorylation sites play a critical role in the transforming capability of Bcr-Abl. It has been shown that the SH2-containing adapter protein Grb2 binds to the autophosphorylation site Tyr(p)177 whereby it couples Bcr-Abl to the Ras pathway. The biological consequences of this interaction, however, are presently unclear. A Tyr177-mutated Bcr-Abl which lacks the ability to interact with the Grb2-SH2 domain still transforms myeloid cells and generates tumors in nude mice. We performed a yeast two-hybrid screen to identify signaling proteins which bind to distinct Bcr-Abl autophosphorylation sites. Autophosphorylation of Bcr-Abl in yeast was accomplished by using the DNA binding protein LexA which permits dimerization and crossphosphorylation of the fused bait. Using a LexA-Bcr-Abl full length fusion protein as bait, we identified several SH2-containing proteins. Among them we confirmed molecules already shown by others to interact with Bcr-Abl, in vivo, including Grb2, PI-3-kinase and Crk indicating that dimerization in yeast leads to autophosphorylation of tyrosine residues crucial for Bcr-Abl signaling in vivo. More importantly, we identified the SH2-containing protein Grb10 as a new binding partner for Bcr-Abl. This binding occurs in a phosphotyrosine-dependent manner at Bcr sites of Bcr-Abl. Both Abl and Bcr alone, as well as a kinase-defective Bcr-Abl, failed to interact with Grb10 in yeast. Mutational analysis uncovered a new SH2 binding site in Bcr-Abl located between Bcr aa242-446, which is different from the Grb2 binding site. Binding could be demonstrated in vitro and also in vivo as shown by co-immunoprecipitation analysis in CML cells. Using a temperature sensitive Bcr-Abl stably overexpressed in hematopoetic cells, we demonstrated that complex formation of Grb10 with Bcr-Abl was kinase activation-dependent in vivo. Notably, a Bcr-Abl mutant protein (Bcr/1-242-Abl) which lacks the ability to interact with Grb10 partially alleviated IL-3 dependence of Ba/F3 cells, indicating that the Grb10/Bcr-Abl interaction is important for Bcr-Abl-induced IL-3 independence of Ba/F3 cells. In addition, the Bcr/1-242-Abl mutant has a reduced capacity to induce focus formation in fibroblasts
PMID: 9747873
ISSN: 0950-9232
CID: 64553

Autonomic manipulation influences both temporal and frequency analyses of late potentials

Schwartzman D; Demopoulos L; Schrem S; Caracciolo E; Perez J; Chinitz L; Slater W
Previous studies of late potentials have not standardized the autonomic milieu at the time of testing. We studied the effects of autonomic manipulation in seven patients with previous Q wave myocardial infarction. Late potentials were evaluated using standard temporal (TD) and spectral temporal mapping techniques (STM) in the drug free state, and during separate intravenous administration of each of the following: isoproterenol, esmolol, and atropine. Isoproterenol was titrated to achieve a heart rate of 130% of baseline. Esmolol was infused at a rate of 250 micrograms/kg per minute, after a loading dose of 500 micrograms/kg. Atropine was given as a 2-mg bolus. In addition, five patients who received no drug infusions acted as controls, undergoing four serial signal-averaging studies in the baseline state: a 'baseline' study, and then three additional studies at time intervals similar to those incurred by the study patients. Therefore, a total of 21 TD and 21 STM tests were done in the study group (seven patients; three drugs per patient) during the drug infusions, and 15 TD and 15 STM tests were done in the control group (five patients; three 'nonbaseline' tests per patient). A change (normal to abnormal, or vice versa) in TD during a drug infusion occurred in 24% of the tests. No such change occurred in the control group (P < 0.01). A change in STM during a drug infusion occurred in 38% of tests, versus 13% of tests in the control group (P = 0.14). Overall, six of seven patients had a change in TD and/or STM diagnosis with infusion of one or more of the study drugs.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 1279625
ISSN: 0147-8389
CID: 13392

Fingerlike mass in the left atrium

Kronzon I; Tunick PA; Schrem SS; Yarmush L
PMID: 2003941
ISSN: 0894-7317
CID: 14169


Kronzon, I; Schrem, SS; Tunick, PA; Slater, J
ISSN: 0009-7322
CID: 31912

Cocaine-induced torsades de pointes in a patient with the idiopathic long QT syndrome [Case Report]

Schrem SS; Belsky P; Schwartzman D; Slater W
PMID: 2220552
ISSN: 0002-8703
CID: 64554

False positive signal-averaged electrocardiogram produced by atrial flutter [Case Report]

Schrem SS; Nachamie M; Weiss E
PMID: 2389709
ISSN: 0002-8703
CID: 64555

Transesophageal echocardiography in the diagnosis of ostial left coronary artery stenosis [Case Report]

Schrem SS; Tunick PA; Slater J; Kronzon I
The diagnosis of ostial stenosis of the left main coronary artery is usually made by use of coronary angiography. However, positioning of the catheter across the obstruction may obscure this diagnosis during contrast injection. Although a damping of arterial pressure when the catheter enters the left coronary artery may suggest ostial stenosis, it may not be possible to make this diagnosis with certainty during cardiac catheterization. We report a series of four patients in whom the left coronary ostium and proximal left coronary arteries were visualized by means of transesophageal echocardiography. Both ostial narrowing by plaque and abnormally fast flow velocities were seen. In each case the echocardiographic findings contributed to the subsequent management of the patients
PMID: 2245029
ISSN: 0894-7317
CID: 63040

Unusual mitral annular vegetation diagnosed by transesophageal echocardiography [Case Report]

Tunick PA; Freedberg RS; Schrem SS; Kronzon I
PMID: 2382626
ISSN: 0002-8703
CID: 63041

The association between unusually large eustachian valves and atrioventricular valvular prolapse

Schrem SS; Freedberg RS; Gindea AJ; Kronzon I
PMID: 2360505
ISSN: 0002-8703
CID: 64556

Metastatic cardiac liposarcoma: diagnosis by transesophageal echocardiography and magnetic resonance imaging [Case Report]

Schrem SS; Colvin SB; Weinreb JC; Glassman E; Kronzon I
The most superior portion of the right atrium is not well visualized by transthoracic echocardiography. This limits the ability of the technique to detect intracardiac disease in this area. We describe a 41-year-old man with a history of liposarcoma in whom transthoracic echocardiography was unable to elucidate a right atrial metastasis. Transesophageal echocardiography demonstrated the morphology and extent of the large right atrial mass. These findings were well correlated with both magnetic resonance imaging and surgery
PMID: 2185795
ISSN: 0894-7317
CID: 36730