The developing story of Sprouty and cancer

Abstract

Sprouty proteins are evolutionarily conserved modulators of MAPK/ERK pathway. Through interacting with an increasing number of effectors, mediators, and regulators with ultimate influence on multiple targets within or beyond ERK, Sprouty orchestrates a complex, multilayered regulatory system and mediates a crosstalk among different signaling pathways for a coordinated cellular response. As such, Sprouty has been implicated in various developmental and physiological processes. Evidence shows that ERK is aberrantly activated in malignant conditions. Accordingly, Sprouty deregulation has been reported in different cancer types and shown to impact cancer development, progression, and metastasis. In this article, we have tried to provide an overview of the current knowledge about the Sprouty physiology and its regulatory functions in health, as well as an updated review of the Sprouty status in cancer. Putative implications of Sprouty in cancer biology, their clinical relevance, and their proposed applications are also revisited. As a developing story, however, role of Sprouty in cancer remains to be further elucidated.

Fig. 1

Representative regulators of the Sprouty cellular content at transcriptional and post-translational level irrespective of the Sprouty isoform and cell type. MAPK/ERK is the main pathway to upregulate Sprouty. Transcription factors WT1 and PPARγ and Wnt/β-catenin signaling pathway have also been shown to upregulate Sprouty. miR-21 is a cancer-associated microRNA that targets and negatively regulates the Sprouty genes. TGFβ1 not only downregulates the expression of Sprouty, but also induces the protein degradation via a lysosome-dependent pathway. E3 ubiquitin ligases c-Cbl, Siah2, NEDD4, and pVHL induce degradation of Sprouty to regulate its cellular content. PP2A competes with c-Cbl for binding to Sprouty, thereby inhibiting c-Cbl-mediated degradation of Sprouty. Mnk1 is a positive regulator of the Sprouty stability through serine phosphorylation. c-Cbl canonical Casitas B-lineage lymphoma; FZD receptor Frizzled receptor; miR-21 microRNA 21; Mnk1 MAPK-interacting kinase 1; NEDD4 neural precursor cell expressed, developmentally down-regulated 4; PP2A protein phosphatase 2A; PPARγ peroxisome proliferator-activated receptor gamma; RTK receptor tyrosine kinase; Siah2 Seven in Absentia homolog 2; WT1 Wilms tumor suppressor 1; CS rearrangement cytoskeletal rearrangement. In this figure, C- and N-terminus of the Sprouty molecule symbol are shown in white and blue, respectively

Fig. 2

Schematic illustration of the Sprouty-mediated regulation of cell proliferation, differentiation, and survival irrespective of the Sprouty isoform and cell type. Sprouty activity is resulted from or regulated through interaction with a number of players. This interaction impacts functionality of ERK and other signaling pathways. Sprouty binds c-Cbl and CIN85 and sequestrate c-Cbl to augment and prolong RTK signaling by inhibiting receptor endocytosis. This mechanism has been implicated in cell differentiation. E3 ubiquitin ligase c-Cbl, on the other hand, binds and induces degradation of Sprouty to restrict ERK activation. Sprouty has also been shown to interact with different phosphatases. It increases active contents of PTEN to mediate antiproliferative actions by inhibiting Akt activation. PTEN is also phosphorylated and accumulated in the nucleus in response to the Sprouty deficiency to induce p53-mediated growth arrest independently of its phosphatase activity. It is likely that the proto-oncogenic potential of NEDD4 is resulted in part from its ability to ubiquitinate both Sprouty and PTEN, resulting in unchecked activation of Akt. Sprouty also increases PTP1B content. However, there is no evidence of direct interaction between Sprouty and PTP1B in RTK dephosphorylation. Phosphatases PP2A and SHP2 differentially regulate the Sprouty activity. Although PP2A potentiates Sprouty binding to Grb2 and thus positively regulates Sprouty by serine dephosphorylation, SHP2 promotes dissociation of Sprouty from Grb2 through tyrosine dephosphorylation and checks Sprouty inhibition of ERK. Moreover, interaction between Sprouty and kinases yields different outcomes. DYRK1A is considered a negative regulator of the Sprouty activity by threonine phosphorylation. TESK1 interferes with Sprouty/Grb2 interaction as well as with Sprouty serine dephosphorylation by PP2A, thereby attenuating Sprouty functioning. Sprouty isoforms also exhibit differential cooperativity with Cav-1 to repress growth factor activation of ERK. At low cell density, however, Cav-1 inhibits the Sprouty function. Sprouty is a general inhibitor of PLC-dependent signaling and inhibits various PKC upstream and downstream signals, including PIP2 hydrolysis. Sprouty is an interacting partner of the Gα _o /GRIN pathway. GRIN modulates Sprouty repression of ERK by binding and sequestering Sprouty. Activated Gα_o, on the other hand, promotes inhibition of ERK via interacting with GRIN and releasing Sprouty. Finally, interaction among the Sprouty isoforms is a mechanism through which oligomers with more potent activity can form. Cav Caveolin-1; c-Cbl canonical Casitas B-lineage lymphoma; CIN85 Cbl-interacting protein of 85 kDa; DYRK1A dual-specificity tyrosine-phosphorylated and -regulated kinase 1A; Gα _o G protein α_o; GRIN G protein-regulated inducer of neurite outgrowth; miR-21 microRNA 21; Mnk1 MAPK-interacting kinase 1; NEDD4 neural precursor cell expressed, developmentally down-regulated 4; PAPC paraxial protocadherin; PIP2 phosphatidylinositol-4,5-bisphosphate; PKC Protein kinase C; PLC phospholipase C; PP2A protein phosphatase 2A; PTEN phosphatase and tensin homolog; PTP1B protein tyrosine phosphatase 1B; RTK receptor tyrosine kinase; SHP2 Src homology-2 containing phosphotyrosine phosphatase; Siah2 Seven in Absentia homolog 2; TESK1 testicular protein kinase 1; HCD high cell density; LCD low cell density. In this figure, C- and N-terminus of the Sprouty molecule symbol are shown in white and blue, respectively. Red lines indicate the Sprouty effect, with dashed lines representing indirect influence. Question marks refer to postulated, but not proven, interactions

Fig. 3

Schematic illustration of the Sprouty-mediated regulation of cell migration, adhesion, and cytoskeletal rearrangement irrespective of the Sprouty isoform and cell type. Sprouty is shown to interact with phosphatases. It increases active contents of PTP1B to mediate its antimigrative action by inhibiting activation of Rac1. Sprouty inhibits the kinase activity of TESK1 that plays a critical role in integrin-mediated actin cytoskeletal reorganization and cell spreading. Sprouty is a general inhibitor of PLC-dependent signaling and inhibits various PKC upstream and downstream signals. Protocadherin PAPC implicated in modulating beta-catenin-independent Wnt-signaling has been suggested to mediate its regulatory effect by binding and sequestering Sprouty. FZD receptor Frizzled receptor; PAPC paraxial protocadherin; PKC Protein kinase C; PLC phospholipase C; PTP1B protein tyrosine phosphatase 1B; RTK receptor tyrosine kinase; TESK1 testicular protein kinase 1; CS rearrangement cytoskeletal rearrangement. In this figure, C- and N-terminus of the Sprouty molecule symbol are shown in white and blue, respectively. Red lines indicate the Sprouty effect