Table 2. ^*Human Melanoma Cells +CVM-1118: Human Phos-MAPK/Phos-Kinases & Cell Stress Arrays.

Increase or Decrease in Phosphorylation of Proteins
↑ Increase	↓ Decrease	Notes
p-HIF-1α ↔	p-Cited-2	↑HIF-1α ↔ Cited-2↓;↓HIF-1α ↔ Cited-2↑ HIF-1α and Cited-2 form a negative feedback loop for HIF-1 activity (Bakker et al., 2007; Du and Yang, 2012). Ectopic Cited-2 expression enhanced tumor growth in nude mice (Du et al., 2012, Du and Yang, 2012). Cited-2 functions as a molecular switch of TGF-a and TGR-β-induced growth control (Chou et al., 2012). Deletion of Cited-2 in mESC results in abnormal mitochondrial morphology and impaired glucose metabolism (Li et al., 2014). Hypoxia induces VM in a number of different tumors. Protein stabilization and nuclear localization of HIF-1α and binding to hypoxia response elements (HRE) in promoters and enhancers of effector genes occurs in response to low oxygen, oncogenes, or inactivated tumor suppressor genes. HIF-1/HRE has been shown to directly modulate VEGF-A, VEGFR, EphA2, Twist, Nodal and COX-2 gene expression, or indirectly modulate VE-Cadherin and Tissue Factor (TF) expression (Kirschmann et al., 2012). It can also modulate the expression of Notch-responsive genes, specifically, stabilizing the NICD protein which interacts with HIF-1α and activates genes with Notch-responsive promotors, including Nodal (Quillard and Charreau et al., 2013)
p-p27 (T198)		p27 is an inhibitor of cyclin E-CDK2 and acts as a tumor suppressor. Phosphorylation of p27 at serine 10 facilitates nuclear export and p27's subsequent proteolysis. Phosphorylation of other sites on p27 impairs the CDK2 inhibitory action of p27. Phosphorylation on T157/T198 impairs import of p27 into the nucleus and promotes cyclin D1-CDR4-p27 complex assembly but, needs activation of the complex by phosphorylation of p27 by Src (Larrea et al., 2008; Wander et al., 2011).
p-c-Jun (S63)		Phosphorylation of c-Jun (Ser63) is associated with apoptosis upstream of Caspase-3 activation (Lei et al., 2004; Ghahremani et al., 2013).
	p-Survivin	An anti-apoptotic protein (smallest member of the “Inhibitor of Apoptosis” [IAP] gene family). Plays a role in apoptosis, cell cycle, chromosome movement, mitosis and cellular stress response. Several tumor suppressors (WT p53, Rb) repress Survivin expression while Ras, STAT3 and Wnt-2 up-regulate its expression. Up-regulation of Survivin inhibits autophagy while down- regulation promotes cell autophagy. Can inhibit apoptosis by inhibiting activity of different caspases (Soleimanpour and Babaei, 2015), and is associated with regulating VM (Sanhueza et al., 2015).
	p-CREB	CREB can be phosphorylated and activated by AKT (Yamada et al., 2015). p-AKT1/2/3 ↓. phosphorylation of CREB promotes interaction with coactivator CBP/p300 inducing cell proliferation, cell-cycle progression and survival of myeloid cells. (Shankar et al., 2005; Braeuer et al., 2011).
	pHSP27	An antiapoptotic protein (Li and Srivastava, 2003). Knockdown of HSP27 decreases the nuclear translocation as well as the activity of NF-κB (Guo et al., 2008; Wei et al., 2011). Phosphorylation of HSP27 inhibits TNF-α induced apoptosis via regulating TAK1 ubiquitination and activation of p38 and ERK signaling (Qi et al., 2014).
	p-38α	More than 100 proteins can be directly phosphorylated by p38 and a significant proportion of them are involved in the regulation of gene expression (Igea and Nebreda, 2015). Rho activation was found dependent on p38 MAPK activity and the presence of HSP27, which is phosphorylated downstream of p38 after arachidonic acid treatment (Garcia et al., 2009). Activation of p38 can lead to the phosphorylation of HSP27 (Huot et al., 1998).
	p-NFκB	NF-κB is the key transcription factor involved in the inflammatory pathway (Chaturveda et al., 2011). Translocation of NF-κB into the nucleus and activity decreases after knockdown of HSP27 (Guo et al., 2008; Wei et al., 2011). The NF-κB pathway is a major downstream target of Notch 1 (Vilimas et al., 2007). WT p53 has been shown to antagonize NF-κB activity (Meylan et al., 2009).
	p-AKT1/2/3	Activates NF-κB (Ozes et al., 1999). mTOR is the most important downstream effector and phosphorylation of ribosomal protein S6 kinase, directly leading to protein translation and cell cycle progression. AKT phosphorylates and deactivates GSK-3β and can downregulate p27 and p21 and also result in the reduction in p53 (Zhang et al., 2015).
	p-TOR	Loss of p53 promotes mTORC2 activation (Laplante and Sabatini, 2012). Following Akt activation, mTOR can be phosphorylated and the activation of this downstream pathway can be important for regulating cell proliferation and differentiation, protein synthesis as well as cell metabolism (Follo et al., 2015). p53 inhibits mTOR activity leading to cell cycle arrest (Jiang & Liu, 2008) GSK activation (dephosphorylation) promotes phosphorylation of TSC2 and β-Catenin, and p-TSC2 suppresses mTOR activity (Hsein et al., 2015).
	p-GSK-3α/β	Activated AKT phosphorylates GSK resulting in GSK inactivation (Takahashi-Yanaga, 2013). GSK-3 phosphorylates p27 to enhance its stability (Surjit and Lai, 2007). GSK activation (dephosphorylation) promotes phosphorylation of TSC2 and β-Catenin, and p-TSC2 suppresses mTOR activity (Hsein et al., 2015).

^*Protein analyses performed in triplicate using R&D Systems Human Phospho-MAPK/Phospho-Kinases & Cell Stress Arrays.