Frasson, Martina (2007) Tirosin-chinasi Src: studi di regolazione/deregolazione in cellule normali e patologiche. [Tesi di dottorato]
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The Src family of protein kinases (SFKs), plays an important role in regulating the signal transduction by cell surface receptors to the cytoplasmic machinery. SFK enzymes are involved in cell grown, differentiation, migration and survival. SFK activity is regulated in the cell by the phosphorylation state of two tyrosine residues and by the binding of protein-partners, that stabilize the kinases in their active or inactive conformation. In normal cells, the SFK activity is tightly regulated and aberration in its mechanisms of regulation can lead to the constitutive activation, which contributes to several pathologies, including cancer.
The aim of this work was to gain deeper insight into the molecular mechanisms, which give rise to the aberrant regulation of SFK activity in two hematopoietic malignancies. Moreover, we analyzed the signaling of Src-kinase Fyn during muscle differentiation.
B cell chronic lymphocytic leukemia is a pathology caused by the accumulation of slowly proliferating cells with defective apoptosis. Our results indicate that, in these leukemics cells,the Src-kinase Lyn is present in its hyperactive conformation as an integral component of an aberrant cytosolic multiprotein complex of 600 kDa. In this complex, the kinase is physically associated with several proteins, such as Hsp90 through its catalytic domain, and HS1 and SHP-1L through its SH3 domain. Treatment of B-CLL cells with geldanamycin, an Hsp90 inhibitor, abrogates cytosolic Lyn activity, induces the kinase degradation and promotes cellular apoptosis.
In platelets of Philadelphia negative myeloproliferative diseases, that are clonal hematopoietc disordes, our data demonstrate that, at variance with normal cells, Src kinase is not phosphorylated at the C-terminus inactivating tyrosine Y527.
This pre-activated conformation of Src is responsible for the basal hypersensitivity of the pathological platelets, which are greatly activated by low thrombin concentrations, which are ineffective towards normal platelets.
In C2C12 murine muscle cells, we demostrated that, in the early phase of the differentiation process, the Src-kinase Fyn phosphorylates the chaperone Grp94 in the lumen of the endoplasmic reticulum. This event is associated with the release of Tyr-phosphorylated Grp94 from the endoplasmic reticulum chaperone protein Grp94 and the chaperone traslocation to the Golgi apparatus and plasma membrane, where Grp94 has been demonstrated to be required for myotube formation.
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