Binding of CIB1 to the αIIb tail of αIIbß3 is required for FAK recruitment and activation in platelets.

BACKGROUND: It is believed that activation of c-Src bound to the integrin ß3 subunit initiates outside-in signaling. The involvement of αIIb in outside-in signaling is poorly understood. OBJECTIVES: We have previously shown that CIB1 specifically interacts with the cytoplasmic domain of αIIb and is required for αIIbß3 outside-in signaling. Here we evaluated the role of CIB1 in regulating outside-in signaling in the absence of inside-out signaling. METHODS: We used αIIb cytoplasmic domain peptide and CIB1-function blocking antibody to inhibit interaction of CIB1 with αIIb subunit as well as Cib1-/- platelets to evaluate the consequence of CIB1 interaction with αIIb on outside-in signaling. RESULTS: Fibrinogen binding to αIIbß3 results in calcium-dependent interaction of CIB1 with αIIb, which is not required for filopodia formation. Dynamic rearrangement of cytoskeleton results in CIB1-dependent recruitment of FAK to the αIIb complex and its activation. Disruption of the association of CIB1 and αIIb by incorporation of αIIb peptide or anti-CIB1 inhibited both FAK association and activation. Furthermore, FAK recruitment to the integrin complex was required for c-Src activation. Inhibition of c-Src had no effect on CIB1 accumulation with the integrin at the filopodia, suggesting that c-Src activity is not required for the formation of CIB1-αIIb-FAK complex. CONCLUSION: Our results suggest that interaction of CIB1 with αIIb is one of the early events occurring during outside-in signaling. Furthermore, CIB1 recruits FAK to the αIIbß3 complex at the filopodia where FAK is activated, which in turn activates c-Src, resulting in propagation of outside-in signaling leading to platelet spreading.

Heterotopic Ossification in Primary Total Hip Arthroplasty Using the Direct Anterior vs Direct Lateral Approach.

BACKGROUND: The formation and severity of heterotopic ossification (HO) may be influenced by type of surgical approach. Our hypothesis was that because of differences in soft tissue dissection, differences exist in HO formation in primary total hip arthroplasty using direct anterior (DA) vs direct lateral (DL) approach. METHODS: A total of 1482 consecutive patients with DL (736) or DA (746) approach and similar perioperative care protocol during 2009-2011 were retrospectively studied. No patient received prophylactic radiotherapy. Preoperative and 6-month postoperative radiographs were reviewed based on Brooker classification. RESULTS: The incidence of overall HO was higher in DL (36.1%) vs DA group (19.4%, P < .001) but high-grade HO (Brooker ≥3) was not significantly different among the groups (3.9% for DL and 3.0% for DA groups). No patient required further surgery for HO resection. CONCLUSION: The type of approach (DA vs DL) did not seem to have a major influence on the short-term incidence of high-grade HO based on this radiographic analysis.

Anatomic Interosseus Membrane Reconstruction Utilizing the Biceps Button and Screw Tenodesis for Essex-Lopresti Injuries.

Longitudinal radioulnar dissociation, also known as the Essex-Lopresti lesion, is a potentially debilitating condition causing painful instability of the forearm that often results from high-injury trauma with compromise of the proximal radius, triangular fibrocartilage complex, and the interosseous membrane. Indications for reconstruction of the interosseous membrane primarily include chronic instability of the forearm. Our reconstructive technique utilizes an anatomic allograft reconstruction with intraosseous fixation, in an effort to biologically reconstruct and anatomically tension the central band of the interosseus membrane.

Attenuation of junctional adhesion molecule-A is a contributing factor for breast cancer cell invasion.

The metastatic potential of cancer cells is directly attributed to their ability to invade through the extracellular matrix. The mechanisms regulating this cellular invasiveness are poorly understood. Here, we show that junctional adhesion molecule A (JAM-A), a tight junction protein, is a key negative regulator of cell migration and invasion. JAM-A is robustly expressed in normal human mammary epithelium, and its expression is down-regulated in metastatic breast cancer tumors. In breast cancer cell lines, an inverse relationship between JAM-A expression and the ability of these cells to migrate on a collagen matrix was observed, which correlates with the known ability of these cells to metastasize. The T47D and MCF-7 cells, which migrate least, are found to express high levels of JAM-A, whereas the more migratory MDA-MB-468 cells have lower levels of JAM-A on the cell surface. MDA-MB-231 cells, which are highly migratory, express the least amount of JAM-A. Overexpression of JAM-A in MDA-MB-231 cells inhibited both migration and invasion through collagen gels. Furthermore, knockdown of JAM-A using short interfering RNAs enhanced the invasiveness of MDA-MB-231 cells as well as T47D cells. The ability of JAM-A to attenuate cell invasion correlated with the formation of increased numbers of focal adhesions and the formation of functional tight junctions. These results show for the first time that an immunoglobulin superfamily cell adhesion protein expressed at tight junctions could serve as a key negative regulator of breast cancer cell invasion and possibly metastasis. Furthermore, loss of JAM-A could be used as a biomarker for aggressive breast cancer.

Junctional adhesion molecules in angiogenesis.

The process of new blood vessel formation from pre-existing vessels is known as angiogenesis. This process is important, both during physiological processes such as development and during wound healing, as well as during pathological processes, such as cancer and arthritis. Understanding the molecular mechanism of the regulation of angiogenesis and the identification of the key players involved in this process may help identify new therapeutic targets to combat and control angiogenesis and hence arthritis and cancer. This review focuses on a recently identified novel cell adhesion molecule, Junctional Adhesion Molecule A, and its role in the process of regulating angiogenesis.