The Met tyrosine kinase receptor and its ligand, hepatocyte growth factor (HGF), play important roles in normal development and in tumor growth and metastasis. HGFdependent signaling requires proteolysis from an inactive single-chain precursor into an active a/b-heterodimer. We show that the serine protease-like HGF b-chain alone binds Met, and report its crystal structure in complex with the Sema and PSI domain of the Met receptor. The Met Sema domain folds into a seven-bladed b-propeller, where the bottom face of blades 2 and 3 binds to the HGF b-chain 'active site region'. Mutation of HGF residues in the area that constitutes the active site region in related serine proteases significantly impairs HGF b binding to Met. Key binding loops in this interface undergo conformational rearrangements upon maturation and explain the necessity of proteolytic cleavage for proper HGF signaling. A crystallographic dimer interface between two HGF bchains brings two HGF b:Met complexes together, suggesting a possible mechanism of Met receptor dimerization and activation by HGF.

Hepatocyte growth factor (HGF), a plasminogen-related growth factor, is the ligand for Met, a receptor tyrosine kinase implicated in development, tissue regeneration, and invasive tumor growth. HGF acquires signaling activity only upon proteolytic cleavage of single-chain HGF into its ␣/␤ heterodimer, similar to zymogen activation of structurally related serine proteases.

This study was aimed to determine the risk factors of Carbapenem-resistant Enterobacteriaceae (CRE) nosocomial infections and assess the clinical outcomes. A case-case-control design was used to compare two groups of case patients with control patients from March 2010 to November 2014 in China. Risk factors for the acquisition of CRE infections and clinical outcomes were analyzed by univariable and multivariable analysis. A total of 94 patients with CRE infections, 93 patients with Carbapenem-susceptible Enterobacteriaceae (CSE) infections, and 93 patients with organisms other than Enterobacteriaceae infections were enrolled in this study. Fifty-five isolates were detected as the carbapenemase gene. KPC-2 was the most common carbapenemase (65.5 %, 36/55), followed by NDM-1 (16.4 %, 9/55), IMP-4 (14.5 %, 8/55), NDM-5 (1.8 %, 1/55), and NDM-7 (1.8 %, 1/55). Multivariable analysis implicated previous use of third or fourth generation cephalosporins (odds ratio [OR], 4.557; 95 % confidence interval [CI], 1.971-10.539; P < 0.001) and carbapenems (OR, 4.058; 95 % CI, 1.753-9.397; P = 0.001) as independent risk factors associated with CRE infection. The in-hospital mortality of the CRE group was 57.4 %. In the population of CRE infection, presence of central venous catheters (OR, 4.464; 95 % CI, 1.332-14.925; P = 0.015) and receipt of immunosuppressors (OR, 7.246; 95 % CI, 1.217-43.478; P = 0.030) were independent risk factors for mortality. Appropriate definitive treatment (OR, 0.339; 95 % CI, 0.120-0.954; P = 0.040) was a protective factor for in-hospital death of CRE infection. Kaplan-Meier curves of the CRE group had the shortest survival time compared with the other two groups. Survival time of patients infected with Enterobacteriaceae with a high meropenem MIC (≥8 mg/L) was shorter than that of patients with a low meropenem MIC (2,4, and ≤ 1 mg/L). In conclusion, CRE nosocomial infections are associated with prior exposure to third or fourth generation cephalosporins and carbapenems. Patients infected with CRE had poor outcome and high mortality, especially high meropenem MIC (≥8 mg/L). Appropriate definitive treatment to CRE infections in the patient is essential.

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