negin28

Integrin is on uPAR to unleash cells

On page 177, Zhang et al. show that the extracellular domain of the 3�1 integrin can hijack a glycolipid- anchored receptor and thus trigger movement of an epithelial cell by inhibiting E-cadherin?mediated cell contacts.
Integrins on epithelial cells are well known to tether the cells to matrix components?laminin-5 in the case of 3�1?but are not usually associated with cell?cell contacts. Zhang et al. show that 3�1 can inhibit cell?cell contacts when 3 binds to the urokinase receptor, uPAR, a known inducer of cell migration in response to certain cytokines. Expression of both uPAR and 3�1 mobilized cells by reducing E-cadherin and -catenin levels at cell junctions, thus dissociating the cells. Other uPAR-induced changes included expression of several genes that are associated with the epithelial?mesenchymal transition, such as the transcription factor SLUG.
The mesenchymal phenotype is a result of localized Src kinase activation induced by the uPAR?3�1 complex. Disruption of Src signaling by overexpression of its protein interaction domains inhibited uPAR-induced cell motility. High uPAR levels are associated with tumor metastasis and a poor prognosis. Since mutations in the 3 extracellular domain that abolish uPAR binding also block motility, mice expressing these mutants may have a better prognosis.

E-cadherin (green) contacts dissolve when uPAR and 3�1 interact (right).

Choreographing telomeres

Telomeres (green) cluster for too long in spermatocytes lacking H2AX.

Telomeres (green) cluster for too long in spermatocytes lacking H2AX.
A histone variant involved in DNA repair and phosphorylated in response to critically short telomeres is nonetheless not involved in most aspects of telomere maintenance, according to Fernandez-Capetillo et al. (page 15). Their results suggest that this histone, H2AX, instead choreographs meiotic telomere movements.Telomeres at the ends of DNA strands are protected by proteins that prevent chromosome fusions. If these proteins are perturbed or if telomeres are severely shortened, the DNA damage response is triggered, repair factors are recruited to telomeres, H2AX is phosphorylated, and chromosome fusions and cell senescence often ensue. H2AX is a target of the ATM kinase, which itself helps to protect shortened telomeres from fusion events.

Given this background, the authors expected that H2AX might also function in telomere maintenance. Instead they found that H2AX mutant cells had telomeres of normal length and had normal chromosome fusion responses to shortened or deprotected telomeres. Telomeres were affected by H2AX loss, however, during a unique organizational stage in which telomeres cluster to form a bouquet-like structure that is associated with the onset of meiotic recombination.

Meiotic H2AX mutant cells were often unable to resolve the bouquet structure, and spermatocyte development frequently stalled at this stage. The group found that the H2AX phosphorylation that occurs in response to recombination- induced double-stranded DNA breaks is reduced in ATM mutants. Dephosphorylation of H2AX might signal that break repair has reached an advanced stage, recombination is near completion, and the bouquet structure can be resolved. This model would explain why development of ATM mutant spermatocytes also stalls in the bouquet stage.

Me in my dad's medical office