Protein constitutive pathway

GPI-anchored proteins constitute a quite diverse family of cell-surface molecules that participate in such processes as nutrient uptake, cell adhesion, and membrane signaling events [3]. All GPI-linked proteins are destined for the cell surface via trafficking through the secretory pathway, where they acquire the... 

Conceivably, lessons learned in yeast on internalization of membrane proteins are relevant to both the constitutive and the inducible pathways of receptor endocytosis in mammals. The constitutive pathway is the least understood, and it may bypass a requirement for ubiquitination by utilizing intrinsic di-leucine and other signals for protein internalization (Covers et al. 1998). In the ErbB family, the pathway may be exemplified by the relatively slow internalization rate of mutant RTKs, either the kinase- defective ErbB-3 (Baulida et al. 1996 Baulida and Carpenter 1997 Waterman et al. 1998), or artificial kinase-defective mutants (Chen et al. 1989 Felder et al. 1990). 

Cells continuously secrete materials via small cytoplasmic vesicles, which in eukaryotes arise largely from the Golgi apparatus (pp. 425-427 Fig. 20-8). The vesicles of this constitutive pathway may have diameters of 50 nm. They carry phospholipids, proteins, and other constituents for incorporation into the plasma membrane of the cell.618 619 In addition, there are... 

In Chapter 11 the effects of binding of hormones to cell surface receptors have been emphasized. Equally important are the mechanisms that control the secretion of hormones. The topic of exocytosis has been considered briefly in Chapter 8, Section C,6 and aspects of the Golgi in Fig. 20-8 and associated text. Both hormones and neurotransmitters are secreted by exocytosis of vesicles. Cells have two pathways for secretion.386 387 The constitutive pathway is utilized for continuous secretion of membrane constituents, enzymes, growth factors, viral proteins, and components of the extracellular matrix. This pathway carries small vesicles that originate in the trans-Golgi network (TGN Fig. 20-8). The regulated pathway is utilized for secretion of hormones and neurotransmitters in response to chemical, electrical, or other stimuli. 

Exocytosis is the secretion of proteins out of the cell across the plasma membrane into the extracellular space. Proteins destined to be secreted are synthesized on ribosomes bound to the RER membrane and are then transported in membrane-bound vesicles to the Golgi apparatus where they are sorted and packaged up into secretory vesicles. All cells continuously secrete proteins via the constitutive pathway, whereas only specialized cells (e.g. of the pancreas, nerve cells) secrete proteins via the regulated secretory pathway in response to certain stimuli. 

Enzymes present in melanosomes synthesize two types of melanin, eumelanin and pheomelanin. Figure 2 illustrates the proposed biosynthetic pathways of eumelanin and pheomelanin. The synthesis of eumelanin requires tyrosinase, an enzyme located in melanosomes. Tyrosinase catalyzes the conversion of tyrosine to dopa, which is further oxidized to dopaquinone. Through a series of enzymatic and nonenzymatic reactions, dopaquinone is converted to 5,6-indole quinone and then to eumelanin, a polymer. This polymer is always found attached to proteins in mammalian tissues, although the specific linkage site between proteins and polymers is unknown. Polymers affixed to protein constitute eumelanin, but the exact molecular structure of this complex has not been elucidated. Pheomelanin is also synthesized in melanosomes. The initial steps in pheomelanin synthesis parallel eumelanin synthesis, since tyrosinase and tyrosine are required to produce dopaquinone. Dopaquinone then combines with cysteine to form cysteinyldopa, which is oxidized and polymerized to pheomelanin. The exact molecular structure of pheomelanin also has not been determined. 

Trophic factors exemplified by NGF and its family members, ciliary neurotrophic factor (CNTF) and glial derived neurotrophic factor (GDNF) all utilize increased tyrosine phosphorylation of cellular substrates to mediate neuronal cell survival. Actions of the NGF family of neurotrophins are not only dictated by ras activation through the Trk family of receptor tyrosine kinases, but also a survival pathway defined by phosphatidylinositol-3-kinase activity (Yao and Cooper, 1995), which gives rise to phosphoinositide intermediates that activate the serine/ threonine kinase Akt/PKB (Dudek et al., 1997). Induction of the serine-threonine kinase activity is critical for cell survival, as well as cell proliferation. Hence, for many trophic factors, multiple proteins constitute a functional multisubunit receptor complex that activates rai-depen-dent and ras-independent intracellular signaling. 

The next step in the transduction process is more problematical. On the one hand, evidence has been adduced indicating that the ETR protein interacts directly with the CTRl protein kinase [64], On the other hand the rapid effects of ethylene on the activation of SMG proteins suggests that these may play a role in linking the receptor to Raf or other protein phosphorylation cascades, as in the case in animals [65-68], The possible role of such proteins is in itself complex since they may not only control pathways separate from protein phosphorylation cascades (e.g. phosphoinositides [69,70] but may themselves interact via GTPase cascades [71]. Equally, it is important to mention that the small GTP-binding proteins constitute a superfamily, the various members of which may have very different functions [72-77]. In neither Arabidopsis [60] nor in peas [59] is it yet clear which member(s) of the superfamily are activated. 

Proteins constitute a universally essential class of macromolecules which perform a wide range of specialized functions in living systems. Examples of these functions include the enzymatic catalysis of metabolic pathways, hormonal signaling in the endocrine system, and antibody mediated defense in the immune system. Proteins also perform critical structural roles, for example as the muscle proteins actin and myosin. The study of protein structure and function is therefore essential to our understanding of life and the advancement of medicine [1]. 

Figure 2. The constitutive pathway for lipid A biosynthesis in E. coli. The genes encoding the proteins which catalyze each reaction are shown. Nine enzymes are required for the biosynthesis of Kdo2-iipid A, also known as Re endotoxin.

---