Deregulated signal transduction by the K1 gene product of Kaposi’s sarcoma-associated herpesvirus

Abstract

The Kaposi's sarcoma (KS)-associated herpesvirus is a lymphotropic virus strongly implicated in the pathogenesis of KS and several lymphoproliferative disorders. The KS-associated herpesvirus K1 gene encodes a transmembrane protein bearing a functional immunoreceptor tyrosine-based activation motif (ITAM)-like sequence; it previously has been proposed to be important in viral tumorigenesis because its expression can trigger cell proliferation in vitro and in vivo. Here we show that expression of the full-length K1 protein can initiate calcium-dependent signal transduction in B cells; however, unlike other ITAM-based signal transduction events, K1 signaling occurs constitutively, in the absence of exogenous crosslinking ligands. This property is caused by its cysteine-rich ectodomain, which when transferred to other consensus ITAMs induces constitutive signaling. Although ITAM-based signaling by K1 involves classical syk and phospholipase C ␥2 activation, both ITAM-and syk-independent signaling pathways are activated by K1 expression. These studies indicate that K1 is a deregulated signaling molecule with pleitropic effects that may explain its known growth deregulatory properties.

Kaposi's Sarcoma-Associated Herpesvirus-Encoded Latency-Associated Nuclear Antigen Modulates K1 Expression through Its cis -Acting Elements within the Terminal Repeats

“…Reduced levels of phospho-Lyn may repress the downstream signaling activities, including phospholipase C␥/Ca 2ϩ pathway activation, thus establishing latency (38). However, previous studies have demonstrated ITAM tyrosine phosphorylationindependent Syc phosporylation and NFAT reporter activation, suggesting that Syc is not the only effector of K1 signal transduction (28,38). Additionally, K1-transgenic mice have been shown to have increased active Lyn kinase but not Syc kinase in splenic B lymphocytes, supportive for Syc-independent phosphorylation of Lyn (38,42).…”

“…K1 protein is related to the immunoglobulin receptor family and has similarity to the B-cell receptor (33). K1 is constitutively active through oligomerization via conserved, extracellular cysteine residues leading to the phosphorylation of the ITAM and recruitment of the major B-cell kinase Syk for the phosphorylation of cellular proteins, mobilization of intracellular calcium, and activation of transcription factors such as NFAT and AP-1 (21,27,28,30,33,38,58). The amino-terminal domain of K1 interacts with the chain of the B-cell receptor complex leading to the inhibition of intracellular transport of B-cell receptor and resulting in retaining B-cell receptor complexes in the endoplasmic reticulum, preventing their intracellular transport to the cell surface which implies a role for K1 in the survival of KSHV-infected cells (26,30,32).…”

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

“…These proteins include EpsteinBarr virus (EBV) LMP2A, murine mammary tumor virus (MMTV) Env, and Kaposi's sarcoma-associated herpesvirus (KSHV) K1 (Caldwell et al, 1998;Lee et al, 1998a;Katz et al, 2005). Studies of signaling by LMP2A (Longnecker et al, 1991;Caldwell et al, 1998;Swart et al, 2000) and K1 (Lee et al, 1998a;Lagunoff et al, 1999) in B cells suggests that these ITAMs are capable of signaling in a manner similar to traditional cellular ITAMs. Additionally, nonhematopoietic cells expressing K1 and LMP2A are susceptible to transformation and in vivo tumor development (Lee et al, 1998b;Scholle et al, 2000;Prakash et al, 2002).…”

The Viral Etiology of AIDS‐Associated Malignancies

“…ITAM motifs are known to be involved in signal transduction on ligand-receptor interaction. However, K1 signaling appears to be constitutive and may be responsible for the activation and proliferation of infected B lymphocytes by inducing phosphorylation of several cellular signal transduction proteins (Lagunoff et al, 1999;Lee et al, 1998a,b). The K1 gene was shown to have transforming activities; it transformed mouse cells in vitro and caused tumors in nude mice (Lee et al, 1998b).…”