Mini-reviewSprouty and cancer: The first terms report
Introduction
The conveyance of signals from receptors to the genetic complement of the cell orchestrates and coordinates all activities of both complex and simple living entities. The first mammalian signaling pathway to be elucidated was the Ras–Erk pathway that is central to many cell processes [1]. A diverse array of growth factors, cytokines and proto-oncogenes transduce their growth promoting signals through the activation of the small G protein Ras, which stimulates the serine–theonine kinase Raf, subsequent to the activation of MEK. MEK then phosphorylates and activates extracellular signal-regulated kinase (ERK). Activated ERK translocates into the nucleus where it regulates gene expression by modulating transcription factors including those of the Ets family [1]. The core protein components of the pathway, as outlined above, are themselves modified by an ever-burgeoning range of support and modifying group of proteins that operate at all levels of the cascade [2]. Several receptor tyrosine kinases, the Ras GTPase and the serine /threonine kinases of the Raf family have all been shown to be the products of oncogenes [3] and are currently the targets of pharmaceutical intervention [4]. In particular, members of the epidermal growth factor (EGF) family of receptor tyrosine kinases (RTKs; including EGFR/ErbB/HER1 and ErbB2/HER2/Neu), FGFRs (fibroblast growth factor receptors) and other tyrosine kinases such as Bcr-Abl are commonly over-expressed in many cancers [3], [5]. Ectopic expression of fibroblast growth factor receptor 3 (FGFR3) associated with t(4;14) has been implicated in the pathogenesis of human multiple myeloma [6]. Activating FGFR3 mutations have been found to contribute to the development of cervical and bladder tumors [7]. Another mechanism of activation of oncogenes are point mutations that enhance the function of the oncogene products by altering critical interacting sequences. Examples include point mutations in Ras oncogene. Mutationally activated forms of Ras such as H-Ras, K-Ras and N-Ras have been shown to efficiently transform cells in vitro and in vivo and such mutations are common in a broad spectrum of human tumors. Mutated variants of Ras (mutations at 12, 13 or 61) are found in 30% of all human cancers, are insensitive to GAP stimulation, and are rendered constitutively active [8]. High rates of K-Ras-activating mutations have been detected in non-small cell lung cancer (15–20%), colon adenomas (40%) and pancreatic adenocarcinoma (95%), making it the single most common mutationally activated human oncoprotein. Oncogenic mutations in B-Raf occur in nearly 70% of melanomas. It is also found at a significant frequency in other cancers, including colorectal, ovarian and thyroid cancers. Over 30 different missense mutations have been identified, with the majority positioned in the B-Raf kinase domain and with 90% corresponding to a V599E substitution [9].
The proteins involved in modifying the core components of the Ras/Erk pathway include a number of specialist scaffold proteins, kinases, phosphatases, ubiquitin-transferring proteins and competitive inhibitors, such as the EGF competing Argos and Kekkon proteins [10]. Another Ras/ERK inhibitor protein, thought originally to be similar in its mechanism of operation to Argos was discovered in Drosophila to modify various Ras/ERK-inducing pathways [11], [12]. The protein, which was later confirmed to be intracellular, was called Sprouty (Spry) because it was involved in modulating branching in tracheal formation and its absence led to random ‘sprouting’ of tracheal tubules.
Genetic evidence and biochemical analysis in cultured Drosophila cells showed that dSpry negatively regulates RTK signaling pathways by inhibiting the Ras/ERK pathway [12]. To date, four mammalian Spry genes have been identified with sequence similarity to the Drosophila protein [11], [13], [14], [15]; these are expressed in the brain, heart, lung, kidney, limbs and skeletal muscle. These proteins have a highly conserved cysteine rich C termini and generally variable N termini that contain several small conserved sequences. As in Drosophila, mammalian Spry proteins work as feedback inhibitors of FGF signaling during organogenesis [13], [15], [16]. Spry1 and Spry4 expression is seen in various mammalian embryonic tissues, including the brain, heart, muscle and gut [15], [17], [18]. The expression of the Sprouty isoforms in the adult tissues can be found in the Unigene, EST Profile Viewer database at the following website (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unigene). Spry proteins play a profound role in regulating tubular morphogenesis such as angiogenesis as well as placenta, kidney and lung development [13], [19], [20], [21], [22], [23], [24], [25].
As the function of Spry proteins has a key role in regulating oncogene-derived proteins, its own expression levels may critically influence the role this protein family plays in the mature organism.
In this review, we summarize the current understanding of Spry regulation in various cancers, the prospect that the expressed proteins have a tumor suppressor function and the potential they may have as a tumor marker.
Section snippets
Sprouty expression is induced by the Ras/ERK pathway
As with negative feedback regulators of signaling pathways, Spry is induced through the same signaling pathway it regulates (Fig. 1). In Drosophila development, dSpry was found to be induced within a subpopulation of epithelial cells that are responsive to FGF, as well as by EGF during embryonic development, namely in the eye disc, the wing imaginal disc and the follicle cells of the ovary [11], [12], [26], [27]. Both loss and gain-in-function experiments in the mouse [15], [21], chicken [17],
Sprouty and mechanism of inhibition of RTK (receptor tyrosine kinase) signaling
It is necessary to understand the mechanism of action of Spry proteins before their importance in various pathways and at various stages of development and disease can be fully assessed and rational therapeutic strategies devised. While several laboratories have reported various interacting proteins and preliminary theories have been advanced, more concrete evidence is needed before a paradigm of action is established [34], [35].
There is a consensus that phosphorylation of a conserved tyrosine
Breast Cancer
In one of the first reports on the possible link between Spry deregulation and cancer, various public databases were interrogated for the expression of Spry1 and Spry2 expression in various cancers. As a follow-up various blots containing matched pairs of normal and cancer tissue were probed. The cancers assessed were from breast, uterus, colon, stomach ovary, lung kidney, rectum and thyroid. Spry1 and Spry2 were consistently downregulated in breast cancer samples (Fig. 3). Real time PCR
Evidence for sprouty isoforms as tumour suppressors
The first evidence of Sprys ability to interfere with the tumourigenic process was shown in a study where over-expression of Spry2 in an osteosarcoma cell line, LM8, was found to inhibit tumour growth and metastasis [43]. Spry2 had been shown to inhibit FGF-induced and serum-induced ERK activation as well as serum- and chemokine-mediated migration in these cells. When hSpry2 overexpressing cells were injected into nude mice, tumour growth and metastasis was suppressed in comparison to control
Melanoma
The Ras/Erk pathway is constitutively activated in melanoma due to oncogenic mutations in B-Raf or N-Ras genes or through autocrine stimulation. Oncogenic mutations in B-Raf occur in nearly 70% of melanomas. It is also found at a significant frequency in other cancers, including cancers of colorectal, ovarian and thyroid origin. Over 30 different missense mutations have been identified, with the majority positioned in the kinase domain of B-Raf and with 90% corresponding to a V599E
Discussion
In multicellular organisms, receptor tyrosine kinases (RTKs) are involved in the control of fundamental aspects of cell physiology, ranging from cell migration to survival, growth, proliferation and differentiation, during development and in postnatal life. The execution of these programs requires signals of adequate strength to be delivered for the appropriate time within precise spatial boundaries. Several RTK inhibitors have been identified in invertebrate and mammalian organisms. Because
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