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The role of epidermal growth factor and its receptors in mammalian CNS

https://doi.org/10.1016/j.cytogfr.2004.01.004Get rights and content

Abstract

Epidermal growth factor (EGF) is a common mitogenic factor that stimulates the proliferation of different types of cells, especially fibroblasts and epithelial cells. EGF activates the EGF receptor (EGFR/ErbB), which initiates, in turn, intracellular signaling. EGFR family is also expressed in neurons of the hippocampus, cerebellum, and cerebral cortex in addition to other regions of the central nervous system (CNS). EGF enhances the differentiation, maturation and survival of a variety of neurons. Transgenic mice lacking the EGFR developed neurodegenerative disease and die within the first month of birth. EGF acts not only on mitotic cells but also on postmitotic neurons, and many studies have indicated that EGF has neuromodulatory effect on various types of neurons in the CNS. This review highlights some of the major recent findings pertinent to the EGF and ErbB family with special references to elucidating their roles in the regulation of neurogenesis, signal transduction and trafficking and degradation.

Introduction

The cells of all living organisms sense their environment and respond to environmental stimuli. Cellular signaling mechanisms govern how information from the environment is decoded, processed, and transferred to the appropriate locations within the cell [1]. Signaling through the receptor tyrosine kinase (RTK) family of receptors regulates a wide range of biological phenomena, including cell proliferation and differentiation. Intracellular communication plays a pivotal role in establishing the cell lineage diversity in multicellular organisms, especially in our brain. At least two classes of molecules are considered to be crucial mediators of this communication. They are insoluble components molecules forming the extracellular matrix or adhesion molecules on the cell surface, and soluble hormone-like messengers, often called growth factors [2], [3]. Because of their importance, such as the EGFR and its ligand, have been extensively studied [1], [2], [3]. EGFR was the first receptor tyrosine kinase to be discovered. Moreover, most of the principles and paradigms that underlie the action of receptor tyrosine kinases were first established for the EGFR. Similarly, many of the mechanisms for activation and recruitment of intracellular signaling pathways following growth factor stimulation were discovered in studies of signaling via EGF receptors. Following the identification of EGFR, three additional members of the same receptor family were identified, ErbB-2, ErbB-3, and ErbB-4. These receptors can be activated by EGF, transforming growth factor alpha (TGFα), and 10 additional potential ligands [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. In this review, we will review some classic findings and recent hot spots of EGFR and its ligands in mammalian CNS.

Epidermal growth factor (EGF) was discovered by Cohen in 1962. He found that injection of crude salivary gland extract into newborn mice induced precocious opening of the eyelids and eruption of incisors [12], he named it as tooth-lid factor. Urogastrone, which inhibits gastric acid secretion from the intestinal mucosa, was isolated from human urine and later identified as EGF [4], [11], [13]. EGF differed from NGF by its ability to induce precocious eyelid opening and incisor eruption resulting from stimulated epidermal growth and keratinization [4], [5], [12]. EGF stimulates the proliferation of ectodermal and mesodermal cells [4], [5], [11]. After 40 years, research based on EGF has expanded at a prodigious rate, focusing on ligands and receptors to human cancers, the development of clinical cancer therapies based on inhibition of these receptors. More recently, an increasing number of reports has shown that EGF is also involved in neurogenesis.

EGF is a single polypeptide consisting of 53 amino acid residues, of which 6 are cysteine [4], [11], [14]. These cysteines form three intramolecular disulfide bonds [15] that are important for maintaining the biological activity of EGF (Taylor et al., 1972). EGF is synthesized as a precursor consisting of 1217 amino acid residues, from which the mature form may be generated by proteolysis [11]. The EGF precursor is a glycosylated transmembrane protein with an apparent molecular weight of 140–150 kDa [4], [11], [16]. This precursor competes with mature EGF for binding to the EGF receptor in fibroblasts, and stimulates the proliferation of mouse keratinocytes as well as the mature EGF. The EGF precursor may have an important role in the cell–cell interaction in vivo [2], [3], [5], [11], [17], [18]. The interactions between the EGF precursor in one cell and the EGF receptor in a neighbor may generate localized biological effects, such as cell migration, cell growth, and morphological change in restricted regions.

Other growth factors with similar structural to EGF can be group in a single EGF family. These molecules include transforming growth factor α (TGFα), amphiregulin (AR), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), and neu differentiation factor, also termed heregulin (NDF/HRG). EGF, TGFα, and amphiregulin only bind and activate EGF receptors (also called ErbB-1 and HER1), and they are referred to as group one of the EGF family. Group two members, which consist of two neuregulins, bind erbB-3 and erbB-4. Group three consists of HB-EGF, betacellulin and epiregulin which bind both EGFR and erbB-4. ErbB-2 does not bind ligands directly but is the preferred heterodimerization partner for all other erbB members [2], [3], [11], [19], [20].

Receptor and cytoplasmic protein tyrosine kinases play a prominent role in the control of a variety of cellular processes during embryonic development and in the regulation of many metabolic and physiological processes in a variety of tissues and organs [8], [21]. EGF and TGFα, amphiregulin [2], [22], [23] bind to EGF receptor (EGFR, HER1, ErbB-1) and induce receptor dimerization, each of the mature peptide growth factors is characterized by consensus sequence consisting six spatially conserved cysteine residues (CX7 CX4–5 CX10–13 CXCX8 C) that form three intramolecular disulfide bonds, and is critical for EGFR tyrosine kinase family [22]. Then, activation of the intrinsic tyrosine kinase induces complex downstream signaling pathways, which can instruct cells either to proliferate, differentiate and/or survive [2], [8], [10], [23], [24], [25], [26], [27], [28], [29], [30] (Fig. 1).

The EGFR is a 170 kDa membrane-spanning protein composed of a 130 kDa single polypeptide chain and N-linked oligosaccharides. The EGFR possesses an intracellular tyrosine kinase domain, which is activated by EGF binding [5], [19]. The EGFR shows a high level of sequence homology with the erbB oncogene product of the avian erythroblastosis virus (v-ErbB) [11]. v-ErbB has the transmembrane and intracellular tyrosine kinase domains derived from the avian EGFR. Namely, the EGFR is the proto-oncogene product of v-erbB. Neu/ErbB-2/HER2, ErbB-3/HER3, and ErbB-4/HER4 are structurally related to the EGFR, which is also called ErbB-1 [11]. These proteins are receptor tyrosine kinases composing the ErbB or EGFR family. The ErbB-2 gene was first identified as a proto-oncogene of the neu oncogene, a transforming gene activated in chemically induced rat neuroectodermal tumors. The erbB-3 and erbB-4 genes have been isolated as homologs of the ErbB-1 and ErbB-2 genes by molecular cloning [6], [11], [31].

EGF, TGFα, AR, HB-EGF, and BTC are ligands for the EGFR and therefore are referred as EGF agonists [11], [32]. NDF/HRG is the ligand for ErbB-3 and ErbB-4. The cognate ligand for ErbB-2 is unknown, although NDF/HRG induces the tyrosine phosphorylation of ErbB-2 as described above [11]. NDF/HRG stimulates the tyrosine phosphorylation of ErbB-2 in some mammary cancer cell lines, but not in ovarian cancer cells and ErbB-2-transfected fibroblasts [11], [31]. It has been reported that NDF/HRG induces ErbB-2 tyrosine phosphorylation presumably through the formation of ErbB-3/ErbB-2 and ErbB-4/ErbB-2 heterodimers [6], [11], [31]. Similarly, EGF stimulates the tyrosine phosphorylation of ErbB-2 through formation of the EGFR/ErbB-2 heterodimer [11], [33]. The heterodimerization and cross-talk of the ErbB family may result in a diversity of effects elicited by the cognate ligand [11], [22].

The ErbB family has also been identified in invertebrates, but there is only one ErbB homologue in each organism. For example, the products encoded by the let-23 [34] and der genes [35] are homologues of ErbB in Caenorhabditis elegans and in Drosophila, respectively. These findings indicate that the multiplicity of the ErbB family members in mammals reflects their complex physiological functions.

Section snippets

EGFR signaling mechanism

The EGFR, a receptor tyrosine kinase, is dimerized, activated, then autophosphorylated on its tyrosine residues, following EGF binding [27]. These phosphorylated tyrosine residues serve as high-affinity binding sites for several secondary signaling molecules containing the src homology 2 (SH2) domain, which consists of about 100 amino acid residues [36], [37]. The interaction between the phosphorylated RTK and the signaling molecule involves the amino acid sequences flanking the phosphotyrosine

EGFR trafficking and degradation mechanism

Activated EGF receptors are removed from the cell surface via endocytosis and subsequent degradation in the lysosome. EGF-induced internalization, degradation and trafficking of the epidermal growth factor receptor (EGFR) mutated at serines 1046, 1047, 1057 and 1142 located in its cytoplasmic carboxy-terminal region. The mechanisms underlying the EGF receptor down-regulation are beginning to be elucidated at the molecular level. The activity of the EGFR declines after reaching the maximal level

General

EGF is synthesized in the submaxillary gland, small intestine, kidney, pancreas, pituitary gland, and brain. EGF is found in body fluids, including saliva, blood, cerebrospinal fluid, urine, amniotic fluid, prostatic fluid, pancreatic juice, and breast milk [5], [9], [11]. EGF was detected by means of radioimmunoassay at concentrations ranging from 0.33 to 0.99 ng/g wet weight of adult rat brain tissue (0.99, brainstem; 0.56, hippocampus; 0.48, cerebellum; 0.33, diencephalon and telencephalon)

Future perspectives

In this review, we have mainly described and the role of EGF and the EGFR in CNS. EGF and EGFR families members have been identified, most of them appear to also exist and function in the CNS. However, information concerning these factors with the exception of EGF and the EGFR in the CNS is still limited. Recently, increasing studies are concerning a molecule called, Erbin and EGFR family in the synapse.

Acknowledgements

This review cannot include all the published EGF work and the authors would like to apologize for not being able to cite all of the primary literature. This work is supported by a grant from the Lee Po Chun Foundation, Hong Kong (2000–2004) to R.W. Wong.

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