The ErbB/HER family of protein-tyrosine kinases and cancer.

Platelet-Derived Growth Factor

The actions of many peptide growth factors include both stimulation and inhibition of cell proliferation, as well as effects unrelated to the control of cell growth. One peptide can have both stimulatory and inhibitory activity in a single cell, depending on the context of the other signal molecules present.

Peptide growth factors are multifunctional

Introduction: Cancer is a devastating disease; however, several therapeutic advances have recently been made, wherein EGFR and its family members have emerged as useful biomarkers and therapeutic targets. EGFR, a transmembrane glycoprotein is a member of the ERBB receptor tyrosine kinase superfamily. EGFR binds to its cognate ligand EGF, which further induces tyrosine phosphorylation and receptor dimerization with other family members leading to enhanced uncontrolled proliferation. Several anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors have been developed, which has enabled clinicians to identify and treat specific patient cohorts. Areas covered: This review covers the basic mechanism of EGFR activation and the role of EGFR signaling in cancer progression. Furthermore, current developments made toward targeting the EGFR signaling pathway for the treatment of epithelial cancers and a summary of the various anti-EGFR therapeutic agents that are currently in use are also pre...

Targeting the EGFR signaling pathway in cancer therapy

EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. Following ligand binding, EGFR stimulates downstream cell signaling cascades that influence cell proliferation, apoptosis, migration, survival and complex processes, including angiogenesis and tumorigenesis. EGFR has been strongly implicated in the biology of human epithelial malignancies, with therapeutic applications in cancers of the colon, head and neck, lung, and pancreas. Accordingly, targeting EGFR has been intensely pursued, with the development of a series of promising molecular inhibitors for use in clinical oncology. As is common in cancer therapy, challenges with respect to treatment resistance emerge over time. This situation is certainly true of EGFR inhibitor therapies, where intrinsic and acquired resistance is now well recognized. In this Review, we provide a brief overview regarding the biology of EGFR, preclinical and clinical development of EGFR inhibitors, and molecular mechanisms that underlie the development of treatment resistance. A greater understanding of the mechanisms that lead to EGFR resistance may provide valuable insights to help design new strategies that will enhance the impact of this promising class of inhibitors for the treatment of cancer.

Understanding resistance to EGFR inhibitors-impact on future treatment strategies.

Localization of epidermal growth factor receptor in hepatocyte nuclei.

The association of polypeptide hormones and growth factors with the nuclei of target cells

One of the liver's principal functions is the formation of bile, which is requisite for digestion of fat and elimination of detoxified drugs and metabolites. Bile is a complex fluid made up of water, electrolytes, bile acids, pigments, proteins, lipids, and a multitude of chemical breakdown products. In this review, we have summarized the source of various biliary components, the route by which they end up in bile, including the underlying subcellular and molecular mechanisms, and their contribution to bile formation. One of the reasons why bile formation is so complex is that there are many mechanisms with overlapping substrate specificities, i.e., many biochemically unrelated biliary constituents share common transport mechanisms. Additionally, biliary constituents may reach bile by more than one pathway. Some biliary components are critical for bile formation; others are of minor significance for bile formation but play a major physiological role. The major driving force for bile formation is the uptake and transcellular transport of bile salts by hepatocytes. The energy for bile formation comes from the sodium gradient created by the basolateral Na+/K(+)-ATPase, to which bile salt transport is coupled. The secretory pathway for bile salts involves uptake at the basolateral surface of the hepatocyte, vectorial transcellular movement, and transport across the canalicular membrane into the canalicular lumen. Hydrophilic bile salts are taken up via a sodium-dependent, saturable, carrier-mediated process coupled to the Na+/K(+)-ATPase. This uptake mechanism is also shared by other substrates, such as electroneutral lipids, cyclic oligopeptides, and a wide variety of drugs. Hydrophobic bile acids are taken up by a sodium-independent facilitated carrier-mediated mechanism in common with other organic ions, including sulfated bile acids, sulfobromophthalein, bilirubin, glutathione, and glucuronides, or by nonsaturable passive diffusion. Two major carrier proteins have been identified on the hepatocyte basolateral membrane: a 48-kDa protein that appears to be involved with Na(+)-dependent bile salt uptake, and a 54-kDa protein, thought to be associated with Na(+)-independent bile salt uptake. The intracellular transport of bile salts may involve cytosolic carrier proteins, of which several have been identified. Some evidence suggests a vesicular transport mechanism for bile salts. Since bile acids clearly do not enter the cell by endocytosis, formation of transport vesicles must be a more distal event in the transcellular translocation process. Some bile salts appear to be transported within the same unilamellar vesicles that are involved in the secretion of cholesterol and phospholipid.(ABSTRACT TRUNCATED AT 400 WORDS)

Subcellular and Molecular Mechanisms of Bile Secretion

Isoflurane is an inhalational anesthetic agent associated with no known hepatic toxicity. Despite this fact, isoflurane has not been widely utilized as an anesthetic agent in studies of liver structure and function in experimental animals. For this reason, livers from rats treated with pentobarbital or diethylether were compared to those from rats treated with isoflurane to determine differences in biochemical and morphologic parameters. Liver from pentobarbital-treated rats showed a significant decline in glutathione-S-transferase activity compared to liver from isoflurane/O2 or ether-treated rats. Liver microsomes from isoflurane/O2-treated rats retained more cytochrome-C(P450)-reductase activity than did those from pentobarbital-treated, ether-treated, or decapitated rats. Despite these biochemical alterations, morphometric analysis of liver from isoflurane/O2 and pentobarbital-treated rats showed no quantitative or qualitative differences in liver structure or organelle volume densities. Neither were differences detected in uptake and distribution of 125I-epidermal growth factor when analyzed by electron microscopic autoradiography. These data show that isoflurane with supplemental O2 has no effects on hepatic structure and fewer effects on hepatic function than other anesthetics and may be a better experimental anesthetic than any currently in use.

Susan Jo Burwen

Papers

Localization of epidermal growth factor receptor in hepatocyte nuclei.

The association of polypeptide hormones and growth factors with the nuclei of target cells

Subcellular and Molecular Mechanisms of Bile Secretion

Isoflurane as an anesthetic for experimental animal surgery

Hepatic receptors and their ligands: problems of intracellular sorting and vectorial movement.