Adaptor proteins for the various growth factor receptors play a crucial role in signal transduction through tyrosine phosphorylation. Several candidates for adaptor proteins with potential effects on the epidermal growth factor (EGF) receptor-mediated signaling pathway have been identified by recent phosphoproteomic studies. Here, we focus on a novel protein, GAREM (Grb2-associated and regulator of Erk/ MAPK) as a downstream molecule of the EGF receptor. GAREM is phosphorylated at tyrosine 105 and 453 after EGF stimulation. Grb2 was identified as its binding partner, and the proline-rich motifs of GAREM are recognized by the Nand C-terminal SH3 domains of Grb2. In addition, the tyrosine phosphorylations of GAREM are necessary for its binding to Grb2. Because the amino acid sequence surrounding tyrosine 453 is similar to the immunoreceptor tyrosine-based inhibitory motif, Shp2, a positive regulator of Erk, binds to GAREM in this phosphorylation-dependent manner. Consequently, Erk activation in response to EGF stimulation is regulated by the expression of GAREM in COS-7 and HeLa cells, which occurs independent of the presence of other binding proteins, such as Gab1 and SOS, to the activated EGF receptor. Furthermore, the expression of GAREM has an effect on the transformation activity of cultured cells. Together, these findings suggest that GAREM plays a key role in the ligandmediated signaling pathway of the EGF receptor and the tumorigenesis of cells.The interactions between receptor tyrosine kinases and adaptor proteins are crucial for the transduction of intracellular growth signals from the plasma membrane to the nucleus: these signals are propagated by the tyrosine phosphorylation of each molecule (1, 2). Among the numerous adaptor proteins, the complex of Grb2 and the Grb2-associated binder (Gab) 2 family protein can directly bind to several growth factor receptors. This complex can also regulate the activity of downstream protein kinases such as Erk and Akt, which are known regulators of various cellular functions (3-5). These adaptor proteins contain functional domains such as the proline-rich, Src-homology (SH) 2, SH3, phosphotyrosine-binding, or pleckstrin homology (PH) domains (1, 6 -8) required for interaction with their partner proteins. In addition, Gab or insulin receptor substrate family proteins have multiple tyrosine phosphorylation sites and are recognized as substrates by tyrosine kinases. Therefore, Gab or insulin receptor substrate family proteins are targets for interaction with other proteins possessing SH2 domains (9).A great deal of excellent work on the epidermal growth factor (EGF) receptor has established the EGF signaling pathway as a paradigm for growth factor-mediated signal transduction (10). The EGF receptor is known for being involved not only in normal cell proliferation but also in the origin or development of various human cancers (11). Many research groups have applied proteomic techniques, such as mass spectrometry, to identify novel molecules and the post-translational mod...

We report the clinical, histopathologic, and immunohistologic features of 15 cases of pseudolymphomatous folliculitis (PLF). The patients comprised seven males and eight females (mean age, 38.6 years; age range, 2-67 years). All patients had dome-shaped or flat-elevated nodules suggestive of cutaneous lymphoid hyperplasias (CLHs). The lesions were solitary in all 15 cases, except in one case with duplex lesions. All lesions were located on the face and measured less than 1.5 cm. In 14 cases with one lesion each, five lesions showed rapid regression after incisional biopsy, whereas the remaining nine underwent excisional biopsy. In the case with duplex lesions, one regressed spontaneously after excisional biopsy of the other. Histopathologically, all PLFs showed dense lymphocytic infiltrates from the dermis to the subcutis simulating cutaneous lymphomas. The walls of hair follicles in all cases were enlarged and irregularly deformed with their epithelium blurred by lymphocytic infiltrates; we called this change "activation" of hair follicles. In nine cases, many atypical lymphocytes were intermingled; three of these cases had been misdiagnosed as cutaneous T-cell lymphoma at other institutions. Immunohistologically, 10 and 5 cases showed predominantly B cells and predominantly T cells, respectively. Remarkably, all lesions showed increased numbers of perifollicular histiocytes expressing anti-S-100 protein and CD1a, and seven lesions showed histiocytes in aggregates. We conclude that PLF is a subset of CLH with characteristic clinical and pathologic features showing perifollicular clustering of T-cell-associated dendritic cells with activation of pilosebaceous units. PLF is an entity to be differentiated from malignant lymphomas and other cutaneous pseudolymphomas.

HLA-DR gene frequencies in 59 Japanese children with juvenile rheumatoid arthritis (JRA) and 62 Japanese adults with rheumatoid arthritis (RA) were analyzed by oligonucleotide DNA typing. As in other studies, the frequency of DRB1*0405 in RA patients was significantly higher than in the Japanese controls. In a comparison of non-classified JRA patients with Japanese controls, no significant differences were observed in the frequency of DR types. However, when the JRA patients were classified into four clinical types, i.e., a rheumatoid factor-positive [RF(+)] polyarticular type, a rheumatoid factor-negative [RF(-)] polyarticular type, a pauciarticular type, and a systemic onset type, DRB1*0405 was found to be significantly higher in the RF(+) polyarticular JRA patients than in the controls (P < 0.05). Thus, the RF(+) polyarticular type of JRA had the same HLA association as RA. This result is consistent with the fact that both RF(+) polyarticular JRA and RA cases have a similar clinical course.